AIDS TREATMENT UPDATE, Issue 43, July 1996
Edward King

- nucleoside analogue reverse transcriptase inhibitors, such as AZT, ddI, ddC, 3TC and stavudine (d4T)

- non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine, loviride and delavirdine

- protease inhibitors, such as saquinavir, indinavir and ritonavir

The nucleoside analogues and the NNRTIs all attack HIV at the same stage in its life-cycle, by inhibiting the HIV enzyme reverse transcriptase.

HIV uses reverse transcriptase during the process of infecting a human cell. HIV carries its genetic material in a form called RNA. After a virus particle has bound to a cell and its RNA has moved inside, reverse transcriptase is used to convert the RNA into the same form as the human cells' genetic material - DNA. It can then integrate with the cell's DNA, completing the process of infection.

Nucleoside analogues interfere with reverse transcriptase's action because the enzyme mistakenly uses them as building blocks when trying to convert the RNA into DNA. NNRTIs also affect reverse transcriptase but in different ways which aren't fully understood.

Besides nevirapine, the other two NNRTIs in advanced development are loviride and delavirdine. In combination with nucleoside analogues they may increase CD4 count and lower viral load, but no studies assessing their effects on disease progression and survival have yet been reported.

* Loviride

Loviride is manufactured by the Belgian drug company Janssen. The Medical Research Council chose to use it in the Quattro trial partly because the risk of rash seems lower than with the other NNRTIs. Quattro is comparing the anti-viral effects of the two drug combination of AZT plus 3TC, the sequential use of AZT, ddI, 3TC and loviride, or the combination of all four drugs.

A trial at the Kobler Centre in London found that the combination of AZT plus loviride led to significant and sustained increases in recipients' CD4 counts. None of 48 participants taking the combination developed HIV strains that were resistant to loviride despite taking it for over two years. The Kobler Centre is now recruiting volunteers with CD4 counts below 150 for another study testing the effects of higher doses of loviride.

Another ongoing trial (known as the Caesar trial) among people with CD4 counts between 25 and 250 who are already taking anti-HIV drugs is studying the clinical effects of adding either 3TC alone, or both 3TC and loviride. Its results are expected at the end of this year.

* Delavirdine

Delavirdine is manufactured by Pharmacia & Upjohn, with the trade-name Rescriptor. Results from several trials were presented at the Third National Conference on Retroviruses and Opportunistic Infections in Washington last January, showing that the combination of delavirdine with nucleoside analogue drugs produced a greater initial fall in viral load and longer-lasting reductions in viral load and increases in CD4 count than seen with nucleoside analogues alone.

Some of these trials are designed to assess the effectiveness of nucleoside analogues with or without the addition of delavirdine on clinical endpoints. Preliminary results presented in Washington looked at all the participants in two trials, regardless of the treatment they received, and suggested that those whose viral load fell by at least 0.5 log for at least 8 weeks after they started treatment had a lower risk of disease progression that people without such a fall in viral load. However, results comparing the effects of the individual drug regimens on viral load have not been released yet.

Nine British clinics (listed on page 7) are taking part in the latest clinical trial of combination therapy with delavirdine. You may be eligible to take part if you have a CD4 count below 350 and are currently taking AZT, ddI or ddC in any combination. Everyone will be given additional 3TC, and half will also receive delavirdine.

People who have received more than six months of prior anti-HIV therapy are ineligible for this trial. By the end of June, Pharmacia & Upjohn hope to have approval for an expanded access scheme to provide delavirdine to people who are ineligible to join this trial, and in the meantime doctors can obtain the drug on a named patient basis.

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