AIDS Treatment Update, Issue 65, May 1998
Megan Nicholson

There is no definitive answer to that question at the moment. Little research has been presented which compares combinations containing two PIs with other combinations. Preliminary results and anecdotal evidence suggest that four-drug combinations including two PIs are very active against HIV. However, in the real world, this may not necessarily be the most effective treatment strategy due to side-effects, non-compliance, drug interactions and/or resistance.

Are combinations including two PIs more likely to suppress HIV to undetectable levels in the long-term than combinations with a single PI? Is it better to sequence PIs (i.e. plan the best way to take them one after another) or combine them? These questions remain the subject of research and speculation.

>>WHAT THE RESEARCH SHOWS

The most common dual PI combination to date has been ritonavir plus the original `hard gel' formulation of saquinavir. Several unrandomised studies have found that a high proportion of people who have not taken a PI before achieve undetectable viral load with this combination. However, the primary aim of this therapy has been to increase levels of saquinavir in the blood to adequate levels. With the advent of the `soft gel' formulation of saquinavir which is absorbed by the body more efficiently, the ritonavir/saquinavir combination is likely to become less common.

Adding one or more new nucleoside analogue reverse transcriptase inhibitors (NRTIs) to dual protease therapy usually produces better anti-viral results than a dual PI combination alone. Early results from a randomised study comparing ritonavir/saquinavir with ritonavir/saquinavir/d4T found that more people had undetectable viral load at week 18 in the triple combination arm (83% versus 64%). The trend suggests the superiority of the triple combination, although the significance and durability of the results are still to be proven.

One of the few sources of comparative data on dual protease therapy is the ongoing Study of Protease Inhibitor Combination in Europe (SPICE) trial. Participants who are already taking NRTIs but have not taken a protease inhibitor before receive either:

- nelfinavir/saquinavir

- nelfinavir/saquinavir plus two NRTIs

- saquinavir plus two NRTIs

- nelfinavir plus two NRTIs.

Researchers say it is too early for a definitive interpretation of the results. However, preliminary results after 8 months suggest that the quadruple combination of two PIs and two NRTIs may be superior to the triple and dual combination arms.

The relative benefits of different dual PI combinations, such as nelfinavir/saquinavir, ritonavir/saquinavir, ritonavir/indinavir or indinavir/nelfinavir, remain unknown.

The use of two PIs may increase the likelihood and severity of side-effects. The accumulation of fat on the stomach and wasting of the face and limbs, called lipodystrophy, is associated with the use of PIs. Preliminary research into lipodystrophy has suggested that people taking a dual PI combination _ in most cases to date this means ritonavir/saquinavir _ may have higher rates of lipodystrophy.

>>WHAT THE DOCTORS RECOMMEND

Doctors contacted by AIDS Treatment Update expressed caution about the use of dual PI therapy, particularly among previously untreated people.

Professor Tony Pinching from St Bartholomew's Hospital told AIDS Treatment Update, "I wouldn't consider dual protease therapy as standard therapy on the present evidence. If a person has run out of other options, then dual protease therapy may be appropriate." Professor Pinching counselled against relying on preliminary data to inform treatment decisions. "At this stage the SPICE results are not compelling and I am concerned that treatment decisions are being made on the basis of trends in early research," he said.

Dr Duncan Churchill from St Mary's Hospital and Dr Graeme Moyle from the Chelsea and Westminster Hospital were less cautious about the potential benefits of dual protease therapy. They acknowledged that some people may want to commence anti-HIV therapy with four drugs including two PIs, and discussed some of the situations in which a dual PI combination might be considered.

1. HIGH BASELINE VIRAL LOAD

If a person has a very high viral load (for example over 100,000), some doctors argue that a combination of four drugs including two PIs might be necessary to achieve undetectable viral load. This is a controversial approach to therapy because the superiority of dual protease combinations is not yet proven.

Dr Moyle told AIDS Treatment Update that if a person's viral load was high, they may be less likely to achieve undetectable viral load on standard triple therapy. "A more potent regimen may be necessary to give people with high viral loads a good chance of going undetectable," Dr Moyle said.

Dr Churchill said he would recommend quadruple therapy including dual PIs for people who had not previously taken anti-HIV drugs if they had very high viral loads. This is despite the fact that a study carried out at St Mary's Hospital showed that most previously untreated people with viral loads over one million, who went on a triple combination including a single PI, reached undetectable viral load at six months. "Our research shows that three drugs will get most people undetectable, but we don't know if it will keep you there," he said. He pointed out that in the AVANTI trial of AZT/3TC/indinavir, over half the participants had measurable viral load (using an ultra-sensitive viral loadtest) at one year. However, it is unclear whether this was because triple therapy was not potent enough, or because of problems with compliance.

Despite his endorsement of dual PI combinations, Dr Churchill is cautious about whether people, especially treatment-naive people who have no HIV-related symptoms, can stick to difficult drug regimens and put up with side-effects in the long term. "It's counter-intuitive that people will put up with those side-effects for years," he said.

2. FAILED ON THERAPY THAT DIDN'T INCLUDE A PI

Another group who may benefit from a dual PI combination are people who experience treatment failure with a combination of NRTIs and/or NNRTIs. Studies among PI-naive people starting on dual PI combinations, and switching at least one NRTI, show that a majority of people achieve undetectable HIV. For example, in a Canadian ritonavir/saquinavir study, about 90% of people remaining on the study at 60 weeks had viral loads below 200. Dr Moyle endorsed this approach to treatment: "A high proportion of people [switching to two PIs] get undetectable viral load even if they have taken NRTIs."

3. FAILED TO ACHIEVE UNDETECTABLE VIRAL LOAD SOON AFTER STARTING ON A PI

If you start a combination including a PI and your viral load does not fall to undetectable levels, you may want to consider adding a second PI or switching to two new PIs. Research suggests that people who switch quickly when the first evidence of viral rebound occurs may have a greater chance of benefiting from second-line protease therapy.

In the early days of PIs, some doctors routinely added ritonavir to a saquinavir-containing combination to try to drive viral load to undetectable. Intensification - adding a drug to a combination which has not achieved undetectable viral load - is now less common than a year or two ago. Research suggests that adding a drug is not as effective as changing a whole combination, although it may provide some benefit.

4. DRUG FAILURE AND VIRAL REBOUND AFTER LONG-TERM USE OF A PI

If a person has taken a PI for months or years and then experiences viral rebound, he or she may still benefit from switching to two new PIs. Decreases in viral load are often seen when protease-experienced people switch to a new dual PI combination, but a smaller proportion of people experience sustained benefit. The likelihood of success may depend on the specific PIs used, whether resistance has developed, and how promptly you switch.

Dr Moyle was cautious about the effectiveness of switching to a dual protease regimen if a person has experienced failure on one PI. He said that the switch from a nelfinavir-containing regimen to ritonavir/saquinavir plus two NRTIs looked relatively good, citing a study in which 13 of 19 people who made this switch had undetectable virus at 6 months. In another study, 7 of 21 people who failed on indinavir or ritonavir had undetectable viral load after 9 months on ritonavir/saquinavir.

Dr Churchill reported modest success with ritonavir/saquinavir after long-term saquinavir use. But extrapolating from these examples is difficult, because many cases of saquinavir failure were due to poor absorption, not to the emergence of resistance to saquinavir. Despite success with saquinavir/ritonavir, Dr Churchill was not overly optimistic about the benefits of dual protease combinations among people with resistance to a PI. "I do use two protease inhibitors in the knowledge that a substantial proportion of those people will not go undetectable and stay there", he said.

Dr Martin Fisher in Brighton reported that the combination of ritonavir/indinavir "is looking promising so far in terms of early viral load reductions", even among indinavir- experienced people. In this combination the drugs can both be given at doses of 400mg twice daily, and it becomes unnecessary to take indinavir on an empty stomach.

5. CAN'T TOLERATE NRTIS

Some people can't take any of the NRTIs due to side-effects, such as peripheral neuropathy, blood abnormalities and impaired liver function, especially among people with late-stage HIV disease and very damaged immune systems. Dr Moyle suggested that for this group of people, a dual PI or PI/NNRTI combination may be a good alternative.

6. HAVE NO OTHER TREATMENT OPTIONS

If a person has resistance or severe side-effects to all the available NRTIs and/or NNRTIs, there is little hard evidence about which treatment options are best. Dr Churchill said that if people have considerable experience with NRTIs and PIs, "you might throw everything you've got at them". A small number of case studies have reported suppression of HIV to undetectable levels using `salvage therapy' of five or more drugs, including two PIs.

>>CONCLUSION

In the future, we may have a better understanding of why certain combinations work for some people but not for others. In the meantime, many questions of treatment strategy remain contentious. Even assuming a combination of two PIs is more potent that a single PI combo, the dilemma remains whether to hit hard, harder or hardest.

Box 1: RESISTANCE AND PROTEASE INHIBITOR EFFECTIVENESS

Current research indicates that the first protease inhibitor(s) you use are crucial in shaping future responses to other PIs. If your first line protease combination does not fully suppress HIV to undetectable levels, preferably to below 50 copies/ml, then some degree of resistance may occur. Consequently, other PIs used in the future, even if used in a double combination, will not be as effective at blocking HIV. Clearly, your first PI choice is very important and it is plausible that a double PI combination may increase your chance of achieving a very low level of virus.

The risk is that if the dual PI therapy fails, you may have accumulated a wider range of resistance mutations, making it less likely that you will respond to any subsequent PIs.

Research on the effectiveness of two PIs among people who have already taken a PI is far from definitive. Studies tend to be small (20 or 30 people) and follow-up is less than a year, so the results aren't as reliable as those of randomised, placebo-controlled trials. Despite the limited information, drug resistance seems to be a key factor in determining the effectiveness of switching to a dual protease combination.

The longer a person has been on a PI, the less likely they are to benefit from switching to a dual protease combination. This is because they are more likely to have acquired several resistance mutations, leading to substantial drug resistance. Substantial resistance to one PI is likely to mean cross-resistance to other PIs.

A low viral load at the time of switching is associated with a greater chance of achieving undetectable viral load with the new combination. Once again, a high viral load suggests the possibility of substantial drug resistance and reduces the likelihood that switching to two PIs will have much effect. Also, large amounts of virus mean that it is easier for drugs to mutate in the presence of drugs and develop a greater degree of resistance.

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