AIDS TREATMENT UPDATE, September 1995
Dr Graeme Moyle

Researchers make a distinction between two types of resistance - genotypic resistance and phenotypic resistance. HIV is said to have genotypic resistance to a drug if tests show that it has the particular mutations in its genetic make-up that have been associated with resistance to that drug. HIV is said to have phenotypic resistance to a drug if laboratory tests show that the virus is significantly less susceptible to the drug's anti-viral effects.

However, it is not clear whether the consequences of developing resistance are always bad for a person's clinical health. First, it is possible that people with AZT-resistant strains may have a relatively poor prognosis because of other factors, such as high HIV viral load. The development of resistance could well be a consequence of that high viral load, rather than the cause. Moreover, in becoming resistant to a drug or combination of drugs, the virus may have to change so much that it is partially crippled or disabled and therefore grows much more slowly and does not damage the immune system so quickly.

When HIV becomes resistant to a drug, the mutations may force the virus to become more sensitive again to a previous therapy, or may delay the emergence of resistance to another drug given in combination. Resistant virus in the blood does not mean all the HIV in the body is resistant to a treatment. Virus in the brain, for example, may remain sensitive for much longer than blood-based HIV, so AZT might still help to prevent neurological problems in someone who has entirely AZT-resistant virus in their blood.

Cross-resistance between some anti-HIV drugs has been reported. This means that virus that has mutated to become resistant to one drug may already be resistant to some other drugs that the individual has never taken. In the future this knowledge may help in deciding how best to use drugs in sequence and which combinations to test.

NUCLEOSIDE ANALOGUES

3TC had previously been reported to turn AZT-resistant virus back into AZT-sensitive virus in test-tube experiments. At the meeting, American and British researchers confirmed that the development of the mutations associated with AZT resistance was reduced or slowed when previously untreated people started treatment with the combination of AZT plus 3TC, as opposed to AZT alone.

However, several researchers reported the appearance of virus that is simultaneously resistant to AZT and 3TC. One study in the USA examined what happened when people who had already been taking AZT for some time started to take 3TC as well. After 12 weeks of combination treatment, 82% of participants had virus that was resistant to 3TC, and 19% were resistant to both 3TC and AZT. However, only 15% had become more sensitive to AZT again. This disappointing news raises doubts about the potential usefulness of 3TC for people who have already taken prolonged AZT therapy.

This study also compared the effects of adding ddC or 3TC to ongoing AZT. Reductions in viral load and increases in CD4 count were initially greater with 3TC, but after 24 weeks viral load reductions in the two groups were similar. No ddC resistance was seen at week 12 in this study. Other US research found that only 3 out of 15 people in a study of the combination of AZT plus ddC developed mutations associated with resistance to ddC by 24 weeks of therapy.

Resistance to ddI, which may result in cross-resistance to ddC, was reported in two studies to develop in half or more of people treated with ddI for around one year. Resistance to ddC or ddI may appear more slowly if they are combined with AZT. HIV that is resistant to 3TC may also be less susceptible to ddC and ddI.

Researchers from Switzerland and France each presented data on the presence of mutations associated with AZT-resistance in newly-infected people with seroconversion illness. In these small studies as many as 15-25% of patients were becoming infected with HIV that was already resistant to AZT, raising concern about the success of safer sex messages amongst people with HIV. It also raises the possibility that for some people, starting therapy with AZT alone may not be ideal as their virus may already be resistant. However, if AZT-resistant virus is no longer exposed to the drug, it tends to become sensitive to AZT again after a period of time.

PROTEASE INHIBITORS

Several protease inhibitors are currently in clinical development, and the appearance of resistant HIV strains has been observed for all of them. However, one of the greatest concerns with the protease inhibitors is the development of cross-resistance.

Earlier this year a report in the journal Nature showed that four people treated with Merck's drug indinavir (also known as crixivan, and formerly as MK-639) developed resistant virus that was cross-resistant to most other protease inhibitors. Similar resistance patterns were reported with Abbott's drug ritonavir (formerly ABT-538) and resistance to this drug was associated with a rebound in viral load. These results imply that people who have been treated with one protease inhibitor may not respond to switching to certain other protease inhibitors later.

However, different resistance patterns, not associated with cross-resistance to other protease inhibitors, were reported with saquinavir (made by Roche) and VX-478 (developed by Vertex and Glaxo-Wellcome). Resistance to saquinavir was seen in around 50% of people receiving this drug (on its own or in combination with other drugs) for 8-12 months. An Italian study has found that the combination of saquinavir and AZT produces better CD4 and viral load responses than either drug alone, and also delays the appearance of resistance to AZT.

CONCLUSIONS

To summarise, recent research has highlighted the following important facts about HIV drug resistance:

- AZT resistance is delayed by combination with saquinavir and 3TC. - Resistance to 3TC appears rapidly, in some cases 're-sensitising' virus to AZT, but in other cases leading to dual AZT/3TC resistance. Resistance to ddC develops more slowly than to ddI or 3TC. - Cross-resistance may develop between some but not all protease inhibitors.

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