AIDS Treatment Update, Issue 63, March 1998
Edward King

In a further development, a new formulation of AZT and 3TC that combines both drugs into a single pill is due to arrive on pharmacy shelves this month. It is the latest move in the drug companies' attempts to come up with easier-to-take combination therapy regimens.

>>Combivir compared with AZT plus 3TC

Each Combivir tablet contains 150mg of 3TC and 300mg of AZT i.e. half the normal daily dose of each drug. So for people who are currently taking AZT and 3TC as separate pills, switching to Combivir will halve the number of pills (from one AZT pill plus one 3TC pill, to a single tablet, every morning and night).

Studies presented in Chicago suggest that combining AZT and 3TC into one pill has not affected either drug's absorption by the body, side-effects or anti-HIV effects, and the tablet can be taken with or without food.

However, a small pilot study comparing people who took AZT/3TC/indinavir with people who took Combivir/indinavir found that Combivir recipients were more likely to achieve undetectable viral load by 16 weeks (abstract 387c). The difference was unexpected, since everyone in the study was essentially being prescribed the same doses of the same drugs; the only difference was that the Combivir recipients took fewer tablets and on a twice daily basis, while those receiving the individual drugs had more pills and were taking AZT on a three times daily schedule. It seems probable that Combivir recipients were less likely to miss or forget doses - in other words, that the combined formulation really did help to improve compliance.

>>Choosing an NRTI combination

The convenience of Combivir is an appealing factor in favour of choosing AZT/3TC as the two NRTI anti-HIV drugs to form the basis of a three- or four-drug combination. However, convenience is not the only factor to take into account when choosing a regimen, and there are good reasons to consider other combinations too, including:

- how effective they are

- their ability to penetrate the central nervous system

- the effects that treatment with one NRTI may have on subsequent treatment with other NRTIs, either because of viral resistance, or other factors

The likelihood of side-effects is another consideration in choosing a regimen. Of all the NRTIs, d4T and 3TC are probably the best tolerated. However, d4T can cause peripheral neuropathy (damage to the nerves in the hands and feet) in up to 20% of recipients, a side-effect it shares with ddC and, to a lesser extent, ddI. Taking d4T/ddI in combination does not appear to increase the risk of peripheral neuropathy. On the other hand, AZT's most common side-effects are nausea, malaise, and shortages of certain blood cells (anaemia and/or neutropenia); these generally affect a small percentage of symptom-free people, but a higher proportion of people with more advanced disease.

>>Comparing efficacy

There was no shortage of trial results presented in Chicago showing that the range of different NRTI combinations, used as dual therapy or as the basis for triple combinations, have comparable effects in reducing viral load. Taken as a whole, these studies found no significant differences between the antiviral effects of AZT/3TC, AZT/ddI, d4T/ddI, ddI/3TC or d4T/3TC. Of all these combinations, AZT/ddI has been the most studied in large clinical trials.

In other words, all the main NRTI combinations appear roughly comparable in terms of their anti-HIV effects in the blood. Even though AZT and 3TC are packaged together in Combivir tablets, they also remain available as single drugs for combining with other NRTIs.

Interestingly, none of these recent comparative studies looked at ddC-containing regimens, perhaps because of trends in several studies suggesting that ddC-containing combinations may be weaker than ddI- or 3TC-containing combinations.

As this issue of AIDS Treatment Update went to press the French national AIDS research agency, the ANRS, issued a press release reporting the results of a trial comparing different NRTI combinations, known as the ALBI trial. Participants with low viral load received:

- AZT/3TC for six months, or

- d4T/ddI for six months, or

- AZT/3TC for three months followed by d4T/ddI for three months

The results showed no benefit from changing treatment after three months. However, at six months more d4T/ddI recipients had achieved viral load below 500 compared with AZT/3TC recipients. No more details are available yet.

>>CNS penetration

The body protects the central nervous system (CNS) from harm by making it relatively hard for many substances to pass from the bloodstream into the tissues or surrounding fluid of the brain and spinal cord. This is known as the `blood-brain barrier'. However, HIV does infect the CNS, so the ideal anti-HIV drug should be able to cross this `barrier'. If only a small amount of drug crosses into the brain, it may not sufficient to suppress the virus fully, and might even hasten the emergence of drug-resistant HIV strains.

Of all the currently licensed NRTIs, AZT penetrates the CNS most effectively, and has been linked to a substantially reduced risk of developing HIV brain disease such as dementia. Small studies have suggested that d4T, 3TC and ddI also cross the blood-brain barrier to some extent, but their effectiveness against dementia has not been proven. The next NRTI drug likely to be licensed, abacavir (formerly known as 1592U89), crosses the blood-barrier barrier about as well as AZT, and is currently being tested as a treatment for dementia.

Thus, AZT currently has the advantage over other NRTIs in terms of CNS penetration. However, the implications of this for the choice and timing of treatment is less clear-cut. Some authorities argue that to protect the brain AZT should be considered as part of every combination, while others suggest that it is best reserved for use in relatively advanced HIV infection, when the risk of dementia is highest.

This may all be less relevant in the era of triple therapy. Recent studies have suggested that various protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can suppress HIV in the CNS, and triple therapy has been linked to dramatic improvements in dementia in some case reports. Potent anti-HIV therapy may also allow the immune system to recover, and this too may reduce the risk of HIV-related brain disease.

>>Resistance profiles

Of all the NRTIs, resistance emerges most rapidly to 3TC. Research consistently shows that 3TC resistance usually develops within a few weeks among people whose viral load remains above the limit of detection while they are taking the drug. However, experts remain divided over the significance of 3TC resistance.

3TC is one of the most powerful of the NRTI drugs, producing quite a substantial drop in viral load up to the point when resistance develops. Afterwards, its antiviral effects are reduced and recipients' viral load typically increases again, but not back to its baseline level. If 3TC resistance is avoided - for example, by using 3TC as part of a potent multi-drug combination - it may be possible to maintain its anti-HIV effects at their full strength for much longer. There is some test-tube evidence (but not much real-world evidence) that 3TC-resistant HIV strains may also be less susceptible to treatment with ddI and ddC.

However, some experts are less concerned about 3TC resistance, pointing to evidence that it may actually have some benefits. 3TC-resistant HIV strains may be less `fit' and reproduce more slowly. The mutation that makes HIV resistant to 3TC may also help to prevent or reverse resistance to AZT.

AZT resistance has been studied in detail, largely because AZT was the first and most widely-used anti-HIV drug. It is caused by an accumulation of HIV mutations which usually take many weeks or months to develop during AZT monotherapy, and are likely to take much longer to develop when AZT is used as part of triple combinations. Several studies of protease inhibitor-containing combinations have demonstrated good responses to treatment among people with AZT resistance.

Resistance to d4T or ddI is relatively rare, for reasons that remain unclear. This is one of the main reasons cited by doctors who favour using d4T/ddI as the first-line choice of NRTIs.

>>Other causes of treatment failure

Other factors (besides viral resistance) that might account for poor responses to NRTI treatment emerged as a major topic of debate at the Chicago conference.

None of the NRTIs are active against HIV until they have been converted into forms called triphosphates by enzymes within human cells. If there are problems with the conversion process, which is known as phosphorylation, not enough of the active form of the drug may be produced. For instance, you might take the correct dose of d4T, but if the d4T is not phosphorylated properly within your cells, levels of active d4T-triphosphate might be too low to stop HIV reproducing.

Some researchers believe that this could explain the results of a study called ALTIS. This trial showed that previously untreated people had better reductions in viral load from the combination of d4T/3TC, compared with people who had taken NRTIs (mostly AZT) before. When they measured levels of d4T-triphosphate or 3TC-triphosphate in a small number of participants, the researchers found that the patients who had taken AZT in the past had lower triphosphate levels than the treatment-na ve patients (abstract 3).

These findings raise the concern that people who have taken AZT may not get the best possible response if they subsequently switch to d4T. However, these findings are very preliminary (based on only six people) and appeared to be contradicted by other studies at the conference. The researchers told ATU that it would be premature to base treatment choices on these findings yet. The research needs to be confirmed in further studies, and there is a wide range of alternative explanations. In particular, it is plausible than people who have taken any NRTI before, whether an AZT-containing or a d4T-containing regimen, may have a reduced response to subsequent NRTIs.

Box: Developing more manageable regimens

By combining their two licensed NRTIs into one drug, Glaxo Wellcome have taken the clearest step to date towards making multi-drug combinations more manageable. However, this is a major focus of research at many companies, and was reflected in reports in Chicago.

Merck's protease inhibitor, indinavir (Crixivan), is currently licensed at a dose of 800 mg three times daily. An ongoing study comparing this regimen with doses of 1000 mg or 1200 mg twice daily found no difference between the doses in viral load or CD4 count during the 32 weeks of treatment (abstract 373).

Roche's new protease inhibitor, nelfinavir (Viracept), currently licensed at a dose of 750 mg three times daily, is also now being studied in a 1250 mg twice daily regimen. Again, there was no difference in viral load responses during 32 weeks of treatment (abstract 374).

While it may be tempting to switch your regimen now, it should be stressed that these are preliminary results. If twice daily dosing is slightly inferior to three times daily, it is possible that differences between the trial groups will not show up until they have been followed for longer.

Trials of once-daily ddI are continuing (see AIDS Treatment Update issue 54). Several drugs in development are also being tested in once-daily regimens, including the NNRTI efavirenz (formerly known as DMP-266 and now available through an expanded access scheme) and adefovir dipivoxil (available in the UK in the ADHOC trial). Other once-daily drugs in early stages of development include FTC (closely related to 3TC) and bis-POC PMEA (related to adefovir).

>>Key conclusions

- The Combivir formulation of AZT/3TC makes that combination more convenient to take

- Other combinations involve more pills, but appear to have equivalent anti-HIV effects

- d4T/ddI may be just as effective as AZT/3TC, and carries little risk of viral resistance

- Early studies suggesting that AZT-experienced people may have poorer responses to d4T remain to be confirmed or refuted

Sidebar: Chicago websites

The abstracts of the research presented at the Chicago conference, and recordings of many speeches, can be found on the Internet at http://www.retroconference.org

Detailed daily summaries of the conference written by leading US doctors can be read at the Healthcare Communications Group site at http://www.healthcg.com

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