Bulletin of Experimental Treatments for AIDS, No. 29; June, 1996
Mark Bowers, Managing Editor of Treatment Publications at the San Francisco AIDS Foundation.

The Food and Drug Administration (FDA) has approved antiretroviral drugs for treating HIV disease from 3 different classes. The first class is nucleoside analog reverse transcriptase inhibitor drugs, often called simply nucleosides, e.g., AZT (Retrovir), ddC (Hivid), ddI (Videx), d4T (Zerit) and 3TC (Epivir). The second class is protease inhibitor drugs, including saquinavir (Invirase), indinavir (Crixivan) and ritonavir (Norvir).

Non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs are a third class of antiviral drugs. On June 7, 1996, an antiviral drugs advisory committee recommended accelerated approval for nevirapine, the first NNRTI to receive such approval. These drugs target the same enzyme as the familiar nucleoside analog drugs, but interfere with the enzyme in a different way. It is not clear exactly how NNRTI drugs work, but it is known that they target the structure of reverse transcriptase to inhibit enzyme activity. Nucleoside analog drugs do not target reverse transcriptase structure; instead they cause premature termination of the viral DNA chain.

Although many different NNRTI drugs have progressed to clinical study, only nevirapine (Viramune, from Boehringer Ingelheim), a-APA (Loviride, from Janssen) and delavirdine (Rescriptor, from Upjohn Pharmacia) have been investigated in Phase III trials. All 3 drug developers are expected to submit data to FDA for marketing approval during 1996. A new drug application (NDA) for nevirapine was filed on February 23, 1996 and the supporting data was evaluated in June; the makers of delavirdine are preparing an NDA; and loviride will be evaluated at the end of the year. Nevirapine and delavirdine have been extensively tested in the U.S., while loviride has been clinically tested only in Europe.

The major issues that face the future development of NNRTI drugs are the rapid emergence of resistance when they are used as monotherapy, cross-resistance with certain other antiviral drugs, and the potential for use in combination with antiviral drugs of other classes.

Resistance and Cross-Resistance

Resistance is the ability of HIV (or any pathogen) to change its chemical structure in order to withstand the effects of drugs used to treat it. Any antiretroviral drug used as monotherapy may breed some level of resistance. Initial studies of NNRTI drugs indicated that viral resistance quickly emerged in monotherapy-treated study participants. Resistance developed more quickly than with nucleoside analog drugs, and dampened early enthusiasm for the whole class of drugs, probably inappropriately.

HIV can become resistant to 2 or more drugs at the same time, resulting in cross- resistance. The cross-resistance patterns of the many antiretroviral drugs from various classes, including nucleoside analogs, NNRTI, protease inhibitors and integrase inhibitors are being continuously evaluated. The National Cancer Institute screens 10,000 synthetic compounds each year for anti-HIV activity. More than 2,500 NNRTI drugs have been screened, and their in vitro resistance patterns mapped against anti-HIV drugs from other classes. Resistance to 1 NNRTI drug usually results in cross-resistance to the entire class. However, clinical benefit may continue even when resistance is detected, through mechanisms that are not currently understood.

The relationship between resistance and how best to treat HIV disease is not yet clear. However, the use of NNRTI drugs in combination with other anti-HIV drugs may be the best strategy to avoid or delay resistance. The cornerstone of most clinical experience with NNRTI drugs is their lack of cross-resistance with AZT. Other possible combinations are also being explored by the drug manufacturers, including combining NNRTI drugs with other approved nucleoside analogs and with protease inhibitors.

The Rationale for Combination Therapy

Combinations of drugs are more effective than monotherapy at reducing viral replication and viral burden. Some combinations demonstrate cumulative or synergistic antiviral effects, such as the combination of 3TC and AZT, or nevirapine and AZT. Furthermore, considerable benefit can be gained from pairing drugs that have opposing resistance patterns: when one drug induces viral resistance, the mutant HIV that is created becomes susceptible to the other drug. A possible role for NNRTI drugs in combination antiviral strategies was framed in 1991 by Douglas Richman, MD, and colleagues, who demonstrated that nevirapine is active against AZT-resistant HIV and synergistic with AZT. Optimal clinical benefit may depend on the selection of antiretroviral drugs that are not cross-resistant. At the Sardinia AIDS Conference in July 1995, S.K. Sharma, PhD, of Upjohn Laboratories, reported that a specific genetic mutation of reverse transcriptase that appears in response to treatment with the NNRTI drug U-104489 produces a virus that is less able to replicate.

Useful combinations of anti-HIV drugs must not include drugs that induce cross-resistance, create synergistic toxicities (augmented adverse side effects) or work against one another because of interactions. Despite the fact that known toxicities of some drugs make them appear to be poor choices for combination, some studies indicate that overlapping toxicities may be managed by reducing the dosages of the drugs. In some cases, expected additive or synergistic toxicities simply have not emerged clinically in the people who are taking the drugs. The combination of d4T and ddI or ddC was predicted to result in more incidences of drug-related peripheral neuropathy because of overlapping toxicities, but increased peripheral neuropathy has not often been seen clinically.

Some of the FDA-approved antiretroviral drugs also have significant interactions with other drugs that are commonly used to treat people with HIV. For instance, AZT interacts with ganciclovir (a drug for treating cytomegalovirus infection) to cause hematologic toxicities, and AZT interacts with fluconazole (a drug used to treat fungal infections) such that blood levels of AZT are significantly increased. These problems can be managed by substituting different drugs that have similar therapeutic effects but do not have interactions with the selected antiretroviral drug, or by altering dosages.

Richard D'Aquila, MD, at Harvard Medical School, cites data that show that viruses with some AZT resistance mutations replicate better than wild-type virus (HIV that has not been exposed to pressure to mutate, e.g., by the use of antiretroviral drugs). The creation of a specific mutation in HIV through the addition of 3TC results in increased sensitivity to AZT, which makes this combination attractive to many people. Additionally, synergism between AZT and nevirapine or delavirdine and many other NNRTI has been demonstrated. What remains to be seen is how durable the effect of combinations of NNRTI drugs with other drugs will be, and the impact on survival and disease progression.

Clinical Data: Nevirapine

Boehringer Ingelheim was recommended for accelerated approval to market nevirapine for the treatment of HIV disease in combination with 1 or more nucleoside analogs on June 7, 1996. Accelerated approval is a drug evaluation mechanism created and regulated by FDA that brings promising drugs for life-threatening illnesses to the market more quickly than the standard drug approval process. Boehringer proposed an indication that would limit the use of nevirapine to HIV positive people who have been previously treated with nucleoside analog drugs and for whom current therapies are deemed inadequate, but the advisory committee recommended wider approval.

To support the request for accelerated approval, Boehringer Ingelheim submitted to FDA clinical 2 surrogate marker studies, data from 2 confirmatory endpoint trials that demonstrate a measurable antiviral effect, and an expanded access protocol initiated in April 1996.

Evaluation of the 2 confirmatory endpoint studies was crucial when FDA decided on the appropriate indication for nevirapine. The indication defines the appropriate patient population and approved reasons to use a drug clinically. Physicians refer to the drug's indication when deciding who is an appropriate candidate for therapy, and insurers often look closely at the indication when they decide whether to reimburse for a prescription. State-run drug reimbursement programs such as the California AIDS Drug Assistance Program (ADAP) also look at the indication when deciding whether a drug should be covered. Physicians are not limited when they write prescriptions for any approved drug as long as the use of the drug is, in their opinion, clinically legitimate.

AIDS Clinical Trials Group (ACTG) 193a, a double-blind, placebo-controlled study, evaluated the differences in survival and clinical AIDS progression in 1,307 volunteers with fewer than 50 CD4 cells/mm3. One of 4 drug regimens was assigned to each volunteer: AZT plus ddI, AZT alternating with ddI, AZT plus ddC, and AZT plus ddI plus nevirapine. The direction of this study was in-fluenced by data that emerged from studies of protease inhibitors and by competition for volunteers when ACTG 320, a study that includes a protease inhibitor (indinavir) or placebo plus open-label AZT and 3TC was opened. The results of study 193a are being analyzed to see what statistically significant differences in survival and in clinical AIDS progression were revealed. Analysis is expected to be completed in June 1996.

Boehringer Ingelheim is now sponsoring study 1100.1090, a large (2,000 persons with CD4 counts below 200 cells/mm3) double-blind, placebo-controlled study in the U.S., Canada, Australia, Europe and South Africa to evaluate survival and AIDS progression. Two triple-drug regimens are offered: AZT or ddC or ddI plus 3TC plus nevirapine, or AZT or ddC or ddI plus 3TC plus placebo.

The use of protease inhibitors in combination with nevirapine will not be permitted until drug interaction studies have shown that the combination is safe. A pharmacologic interaction study of saquinavir plus nevirapine is underway. The primary concern is to determine if nevirapine will significantly reduce plasma levels of saquinavir, or vice versa. Because of the way in which these 2 drugs are metabolized, saquinavir would theoretically be most likely to be affected by the co-administration of nevirapine. Other protease inhibitors are expected to be less affected by the induction brought about by nevirapine. Preliminary data from the interaction study was available for presentation at the June FDA advisory committee hearing. Although not conclusive, the interaction between saquinavir and nevirapine seems mild so far.

Of particular interest to the antiviral advisory committee were preliminary data from a study of the administration of a single dose of nevirapine to HIV infected pregnant women when they begin labor, followed by a single dose later given to the newborn. Because the serum concentrations of nevirapine are so reliable, because the drug crosses the placenta easily and is found in therapeutic concentration in the umbilical cord, and because the half life of the drug is comparatively long, nevirapine may provide protection against mother-to-infant transmission comparable to that seen with the perinatal administration of AZT. Preliminary data indicate that therapeutic levels of nevirapine are maintained in the mother's colostrum (first breast milk) after only 1 dose of nevirapine.

In order to persuade FDA to grant marketing approval for nevirapine, Boehringer Ingelheim needed to demonstrate that:

* A serious medical need not met by currently available therapies can be filled by nevirapine

* The use of nevirapine provides meaningful benefit beyond what is available with existing treatments

* Nevirapine has a favorable impact on survival or disease progression in some identifiable group of patients.

Maureen Myers, MD, the person in charge of nevirapine development at Boehringer Ingelheim, says, "the way to use nevirapine to maximum effect is to avoid the emergence of resistance, and in so doing, minimize viral replication."

An expanded access protocol for nevirapine has been established for those who are ineligible or unable to participate in the current active clinical studies. Contact the Viramune Expanded Access Program at 1-800-595-5494.

Delavirdine

Few published clinical data support an application for accelerated approval for delavirdine. However, the analysis of the data collected so far from Upjohn protocols 0017 and 0021 illustrate the potential benefits of delavirdine in combination with nucleoside analog drugs. Upjohn protocol 0021 was a randomized, double-blind 2-year dose-response study in volunteers with CD4 counts between 200 and 500 cells/mm3. The study compared 200 mg, 300 mg and 400 mg of delavirdine 3 times a day in combination with AZT. The study also included an AZT-only group. Because data from ACTG 175 and the European Delta Study showed that AZT monotherapy was less effective than AZT plus ddI, AZT plus ddC, or ddI monotherapy, participants in the AZT-only group and those in the 200 mg delavirdine group are being re-randomized to receive the triple combination of AZT plus 3TC plus either placebo or delavirdine at 400 mg 3 times a day. The difference in effect of the triple combination of AZT plus 3TC plus delavirdine compared to AZT plus 3TC will be measured by CD4 cell counts, ICD p24 antigen levels, and HIV RNA and DNA levels measured by polymerase chain reaction (PCR).

A preliminary look at the data from 800 participants enrolled in protocol 0021 showed an average 20 cell/mm3 increase from baseline CD4 cell count sustained for more than 1 year and a long-term decrease in viral burden (more than 1 year) as measured by HIV RNA levels of greater than or equal to 0.5 log. Viral burden decreases were noted for up to 60 weeks. The group receiving 400 mg of delavirdine 3 times a day showed the greatest reductions in viral burden. Interestingly, the participants who saw a 0.5 log reduction in viral burden by the eighth week of treatment were about 2.5 times less likely to progress to AIDS or death after 60 weeks. The response to treatment also appears to depend on the magnitude of viral burden at entry into the study; for participants with a viral burden greater than 5 logs at entry, a treatment-associated decrease in viral burden of 0.5 log for as little as 8 weeks reduced the incidence of disease progression by 50% or more.

Upjohn protocol 0017, begun in April 1994, is a double-blind, randomized, comparative study of delavirdine in combination with ddI versus ddI monotherapy. The same surrogate markers are being used to evaluate this study as are used in protocol 0021. Study participants have lower CD4 counts (between 0 and 300 cells/mm3), and may have had unlimited exposure to AZT and less than 4 months of prior ddI use. About 400 participants are now registered in each of 2 study arms. One arm offers 400 mg of delavirdine 3 times daily plus ddI at 200 mg twice daily to participants who weigh more than 60 kg, or 125 mg twice daily to those who weigh less than 60 kg; the second arm offers placebo plus ddI by weight, as above.

ACTG 261, begun in September 1994, is a Phase II, randomized, double-blind trial of delavirdine in combination with AZT and/or ddI versus AZT monotherapy versus ddI monotherapy for participants with CD4 counts from 100-500 cells/mm3 and less than 6 months prior AZT or ddI use. The study of 549 volunteers will continue for 48 weeks; analysis of data is not expected until early 1997.

Important drug interactions with delavirdine include rifampin and rifabutin, and the antihistamines terfenadine (Seldane), astemizole (Hismanal) and loratidine (Claritin). Clarithromycin can be used instead of rifabutin to prevent Mycobacterium avium complex (MAC). The use of ddI decreases the absorption of delavirdine. To manage this interaction, delavirdine should be taken 1 hour before taking either ddI or antacids. Delavirdine is now available through an expanded access program for HIV positive people over 13 years old who have CD4 cell counts ranging from 0-300 cells/mm3, are failing to respond to other therapy and are receiving at least 1 other antiretroviral drug. Physicians may contact the Delavirdine Expanded Access program at 1-800-779-0070.

Loviride

The European clinical experience with Janssen Pharmaceuticals' non-nucleoside reverse transcriptase inhibitor has been more extensive than American clinical experience. In one study, loviride monotherapy was compared to AZT monotherapy, loviride plus AZT, and 3 months of placebo followed by 3 months of loviride monotherapy in a 6-month double-blind study of 56 volunteers with CD4 cell counts between 200 and 500 cells/mm3 and some prior AZT experience. Quantitative PCR measures of HIV RNA in peripheral blood revealed that the combination arm of the study had an average 1 log drop in viral load from baseline to week 8.

A second 6-month double-blind, placebo-controlled study of 114 participants with no prior antiretroviral drug experience and CD4 cell counts less than 400 cells/mm3 compared the effects of R18893 (another NNRTI drug) at 200 mg 3 times a day to loviride at 100 mg 3 times a day or to placebo. CD4 cell counts rose 15% over baseline measurements after 8 weeks on loviride and were sustained for at least 6 months.

A current Phase III study of loviride compares AZT monotherapy, AZT plus 3TC and AZT plus 3TC plus loveride. Janssen is expected to submit collected results of clinical studies to FDA for an NDA in late 1996 or early 1997.

Drug Approval Considerations

Since both nevirapine and delavirdine have time-limited anti-HIV activity, it will be important for the drug manufacturers to show where NNRTI drug use is of greatest utility. One consideration is the relatively few side effects and drug interactions that accompany the use of NNRTI drugs when compared to the more powerful protease inhibitor drugs. A key issue for FDA to consider when deciding whether to give other NNRTI drugs accelerated approval is that they demonstrate considerable clinical benefit by reducing viral load at nearly any point in HIV infection.

The most complex issue involving the potential use of NNRTI drugs is to settle on a group or groups of patients who will likely benefit from a combination therapy that includes an NNRTI. Theoretically, a combination of drugs that work at different stages of the viral life-cycle may more effectively delay the emergence of resistance and prolong inhibitory activity, producing clinical benefit.

What benefit can NNRTI drugs really offer? Clinical experience so far is somewhat puzzling; although resistance to NNRTI drugs can emerge as quickly as days to weeks after starting them, reductions in viral load continue after resistance has been documented. Do the drugs in this class exert selective pressure on HIV to hold down the rate of replication even as resistance increases?

The answers to these questions probably depend on individual responses to antiretroviral combinations, and the use of NNRTI drugs should be evaluated on a case-by-case basis.

Other NNRTI Drugs

Several other NNRTI drugs are in earlier stages of development and evaluation. HBY097 (Hoechst Roussel and Bayer) is in Phase I/II testing at Stanford University; this is a novel NNRTI that produces a specific genetic mutation in HIV in the test tube that may correlate with the emergence of a less virulent virus. Thomas Merigan, MD, principle investigator for the study, is looking for the mutation and the durability of the drug's antiviral effect. If the mutation consistently appears, it will be necessary to demonstrate that the resulting virus is less able to cause HIV disease progression or leads to increased survival, questions which are open at this time.

Conclusions

The number of approved antiretroviral drugs has increased significantly in the last few years. As the number increases, the number of possible combinations increases as well. Experience has taught clinicians that the best strategy for managing HIV disease is individualized therapy. Individualized therapeutic strategies can be evaluated for their continuing effectiveness by periodic reference to the results of viral load tests, such as branched-chain DNA and PCR assays.

For some people, NNRTI drugs will significantly reduce viral load, and it will remain low for long periods. These are the best candidates for NNRTI drug use. It remains for clinical studies to pinpoint who will benefit most, and for FDA to provide guidelines through the wording of the individual drug indications.

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