The Moving Target of Antiretroviral Therapy

The FDA approved 3TC (Lamivudine) and saquinavir in November, 1995, and then approved ritonavir and indinavir on March 1, 1996. This sudden expansion of the armamentarium of drugs for HIV is viewed as a major breakthrough for HIV therapeutics. It is also a time of great confusion for care providers since the experience with the new drugs and drug combinations is limited, the cost is high and guidelines are limited.

The early feedback from HIV authorities in various parts of the country suggest the following are likely to represent the most common regimens, at least for the immediate future:

1. AZT (200 mg tid) plus 3TC (150 mg bid) plus either indinavir (800 mg tid) or ritonavir (600 mg bid).
2. AZT (above dose) plus ddI (200 mg bid) or d4T (40 mg bid) plus indinavir or ritonavir (above doses).
3. Nucleoside analog (AZT, ddi, ddC or d4T) plus indinavir or ritonavir.

These suggestions are not necessarily "right," but represent a consensus regarding the options for combination therapy using currently available drugs. Several issues are important to emphasize in terms of both guidelines and gaps in knowledge.

Selection of protease inhibitors: Saquinavir has a notable disadvantage of poor bioavailability, although the future of this drug still appears promising based on the probability of a new formulation and a favorable drug interaction with ritonavir. The preferred agents in this class are indinavir and ritonavir; both have extraordinarily potent anti-HIV activity. An advantage for ritonavir is that it is the only protease inhibitor to receive "traditional approval" from the FDA based on their study showing benefit based on clinical outcome, i.e. prolonged survival and a delay in AIDS-defining diagnosis. Saquinavir and indinavir received "provisional approval" based on demonstrated benefit with surrogate marker endpoints only. Indinavir has the advantage of better GI tolerance. Ritonavir has an extraordinarily complicated list of drug interactions due to profound inhibition of cytochrome P450 isoforms. This results in 23 entries on the "forbidden drug list" for concurrent administration.

Monotherapy

Most authorities feel that single drug treatment of HIV infection is passe. Nevertheless, there are some patients who have done well with monotherapy drug treatment in the past, and many authorities see little reason to change regimens in such patients. In addition, there are some patients who will simply not be able to comply with the complexity or support the cost of combination treatment. Perhaps the favored regimens for monotherapy are ddI (based on ACTG 175) and d4T (based on good patient acceptance and demonstrated benefit in patients who are AZT experienced).

CNS Penetration

AZT is the only drug currently available for treatment of HIV which shows good penetration across the blood-brain barrier. This has persuaded some authorities to favor inclusion of AZT in regimens for patients who tolerate the drug even if there have been long periods of prior exposure.

Antiviral Effect

In vitro studies and, to some extent, in vivo experience, show that nucleoside analogs reach a saturation point with antiviral levels achieved using commonly recommended doses. By contrast, protease inhibitors show increasing antiviral activity with increasing doses so that the major limitation with these drugs is cost, side effects and "pill burden."

Resistance

Resistance is expected to be a major problem with all anti-HIV agents but is expected to be particularly problematic with protease inhibitors. There is rapid and high grade resistance at six months in about 50% of patients treated with indinavir alone, but only in 6% of those who receive indinavir plus a nucleoside analog. The same applies to a large extent with ritonavir. For this reason, these drugs will be advocated for use only in combination with other agents, and the course should not be interrupted. With AZT, resistance is noted in approximately 50% who have received the drug for two years. Variables that influence the rate and extent of AZT resistance are stage of disease, duration of treatment and viral burden. The frequency of resistance in "community strains" is now approximately 10%. After discontinuation, there is often recovery of sensitivity, but resistance is noted again within two weeks of readministration. With 3TC, the 184 codon mutation results in profound resistance to 3TC, recovery of sensitivity to AZT, and modest cross-resistance to ddI and ddC. Resistance tends to develop slowly and is low grade in regimens with ddI, ddC or d4T plus saquinavir. These observations account for much of the theory behind the advocated combinations noted above.

There are no clear guidelines for the time to initiate or change therapy based on CD4 cell count, CD4 cell slope or viral burden. These issues will be addressed in future issues of the Moore News.