Published in the Bulletin of Experimental Treatments for AIDS April 1999 issue, by the San Francisco AIDS Foundation.

Selected Highlights from the 6th Conference on Retroviruses and Opportunistic Infections
-- Main Page
-- Clinical Research
-- Protease Inhibitor Side Effects
-- Anti-HIV Drugs and Combinations
-- HIV Transmission and Origins
-- HIV-Related Conditions

April 1999 Table of Contents

Main Page

beta@sfaf.org

Selected Highlights from the 6th Conference on Retroviruses and Opportunistic Infections

Anti-HIV Drugs and Combinations

By Harvey S. Bartnof, MD

• Double Protease Inhibitor Combinations
• T-20 (Pentafuside)
• Adefovir dipivoxil (Preveon)
• ABT-378
• Amprenavir (Agenerase)
• Indinavir (Crixivan)
• Nelfinavir (Viracept)
• Ritonavir (Norvir)
• Saquinavir (Fortovase)
• Tipranavir
• Nevirapine (Viramune)
• Delavirdine (Rescriptor)
• Efavirenz (Sustiva)
• Abacavir (Ziagen)
• d4T (Zerit)
• ddI (Videx)

Promising New Double Protease Inhibitor Combinations Reported

Certain aspects of combination regimens with indinavir as the sole protease inhibitor present difficulties for some people with HIV. These include food restrictions and fluid requirements, total daily pill burden, and the three-times-daily dosing. A double protease inhibitor combination using 400 mg of indinavir and 400 mg of ritonavir, each twice daily, plus two nucleoside analogs has been gaining popularity since first proposed by Cassy Workman, MD, from Sydney, Australia. This regimen allows the two protease inhibitors to be taken twice daily with no food restrictions or fluid requirements. The combination has shown extreme potency for both treatment-naive and treatment-experienced persons, and has not been associated with kidney stone formation to date for the 79 participants who have taken the therapy for a mean of 34 weeks.

Several researchers at CROI reported on other possible twice daily indinavir/ritonavir regimens, including 800 mg indinavir plus 100 mg ritonavir twice daily (Burger), 800 mg indinavir plus 200 mg ritonavir twice daily (Saah), and 800 mg indinavir plus 400 mg ritonavir twice daily (Saah). There are favorable drug interaction characteristics specific to each of these combinations. Clinical trials comparing the different doses will be necessary to determine which is the best. Another double protease inhibitor combination worth watching is 1,200 mg indinavir plus 1,250 mg nelfinavir twice daily (Squires). The therapeutic possibilities seem almost endless.

T-20 (Pentafuside)

Phase II Results for T-20

• Phase II results of T-20 indicate moderate anti-HIV activity.
• T-20 is the first HIV fusion inhibitor to complete phase II testing.

The first drug in a new class of anti-HIV drugs called fusion inhibitors has moved along the trial pipeline into phase III studies (see BETA, January 1999). T-20, also called pentafuside, is synergistic with protease inhibitors and nucleoside analogs. Synergy is an enhanced anti-HIV effect when drugs are combined that is greater than the additive effects of the individual drugs.

The CROI report on a one-month phase II trial of T-20 was authored by Jay Lalezari, MD, of Quest Clinical Research in San Francisco. Data were presented by Joseph Eron, MD, from the University of North Carolina. All 78 persons enrolled had significant prior anti-HIV therapy, including a mean of nine antiretroviral drugs and three protease inhibitors. Participants entered the trial with either a stable background of combination anti-HIV therapy or no therapy. All participants were required to have a baseline HIV RNA viral load greater than 5,000 copies/mL. At the beginning of the trial, the mean baseline HIV viral load was five log copies/mL, while the mean CD4 cell count was 117 cells/mm³. The daily dose of T-20 ranged from 12.5 to 200 mg. It was given either by a continuous infusion pump implanted under the skin or self-administered twice daily by injection under the skin.

The results demonstrated a dose-related reduction in HIV viral load. The maximum viral load reduction was 1.6 log copies/mL. Greater and more durable viral load reductions occurred among those with a baseline viral load less than 100,000 copies/mL. T-20 was reported to be well tolerated, with no severe or life-threatening side effects. However, two persons (3%) withdrew from the study due to side effects. The most common of these were redness and hardness at the site of the injection or infusion. One person developed a rash. Three persons withdrew because they did not tolerate the subcutaneous infusion pump. Over one-third of those in the infusion pump arm switched to subcutaneous injection. Twice daily self-injection was preferred to the infusion method by most persons. The effective dose of T-20 appears to be 50-100 mg twice daily.

The viral load reductions achieved in this phase II trial are impressive given the antiretroviral therapy experience of the participants. T-20 will likely have even greater benefits when used in combination therapy with drugs that are not part of a failing regimen. Phase III trials of T-20 have already begun. The drug has been given "fast track" status by the FDA for accelerated approval. Several poster presentations on other fusion inhibitors in clinical development were also presented at CROI (see Drug Watch in this issue of BETA).

Adefovir dipivoxil (Preveon)

Benefits of Adefovir

• 60 mg dose of adefovir was reported to have benefits similar to 120 mg dose.
• Less kidney toxicity occurs with lower dose.
• All persons in expanded access protocol will now receive 60 mg.
• A New Drug Application (NDA) will be submitted to the FDA by June 1999.

Several presentations regarding adefovir dipivoxil (Preveon) were given both at CROI and the 12th International Conference on Antiviral Research held in Jerusalem on March 21-26, 1999 (see also BETA, October 1998). Adefovir is the first drug in the nucleotide analog reverse transcriptase inhibitor class. Based on clinical trials to date, Gilead Sciences plans to submit an NDA for adefovir to the FDA by the end of the second quarter of this year. Until it is approved, adefovir is available through an expanded access program. The dose of adefovir is once daily with 500 mg of L-carnitine, a nutritional supplement. Adefovir also has activity against hepatitis B virus and cytomegalovirus (CMV).

A four-week monotherapy trial (study 420) using a once daily dose of 60 mg in treatment-naive persons led to an HIV viral load reduction of 0.25 log copies/mL, similar to that observed with a 120 mg dose. In the double-blind study, the control arm (taking no anti-HIV drugs) sustained a viral load increase.

Study 417 included 211 treatment-experienced participants who were randomized to receive 60 mg or 120 mg of adefovir as part of a triple-drug regimen; the other two drugs were nelfinavir and saquinavir (Fortovase). Those who also received a fourth drug were not included in the current analysis. After 20 weeks of therapy, 42% of those in the 60 mg arm and 33% of those in the 120 mg arm achieved an undetectable HIV RNA viral load (limit of quantitation 400 copies/mL). The results were not significantly different. CD4 cell count increases were approximately 80 cells/mm³ in each arm.

The rate of proximal renal tubular dysfunction (PRTD), a type of kidney toxicity, was lower in the 60 mg arm after 42 weeks. Abnormal increases in blood creatinine (indicative of impaired kidney function) occurred in 29% of persons in the 60 mg arm and 42% in the 120 mg arm. Similarly, abnormal decreases in blood phosphate (a salt normally retained by the kidney) occurred in 26% of persons in the 60 mg arm and 49% in the 120 mg arm. Both differences were statistically different. Fortunately, PRTD is mostly reversible, especially if detected early.

Due to relatively equivalent benefits when comparing the two doses, and the reduced kidney toxicity in the lower dose arm, the adefovir expanded access protocol has been modified. All persons currently in the program, and any who enter in the future, will receive the 60 mg dose; no one will receive the 120 mg dose. The NDA will be for a dose of 60 mg. The indication sought will be "for the treatment of HIV-infected persons with clinical, immunologic, or virologic progression despite prior reverse transcriptase inhibitor therapy."

The toxicity of adefovir for participants in the expanded access program was well characterized at CROI by Sally Nuessle, MD, and colleagues. Over 5,800 persons (10% women; 30% non-Caucasian) were included in the analysis. All had extensive prior anti-HIV therapy. A total of 16% withdrew from adefovir therapy, including 7% due to adverse events. These adverse events included gastrointestinal toxicities (3%) and kidney toxicities (2.5%). Another 5% withdrew voluntarily. Four percent experienced HIV progression. Less than 1% of participants died. Rare serious adverse events (less than 1% each) included pneumonia, kidney toxicity, pancreatitis, fever, and nausea with or without vomiting.

Researchers at CROI presented other information about adefovir. In study 411, a lack of adefovir resistance mutations was found in 18% of treatment-naive persons who experienced HIV viral load rebound after 20 weeks of various adefovir/indinavir three- and four-drug combinations. In addition, researchers reported on a significantly increased response to adefovir combination therapy in persons whose HIV strains had genetic resistance to 3TC, and a very good response to adefovir in persons whose HIV was resistant to both 3TC and AZT through 48 weeks (study 408). None of the 219 persons in the study had HIV strains that developed adefovir resistance mutations.

ABT-378

ABT-378 Combination Shows Significant Benefits at 20-24 Weeks

• ABT-378 is an experimental protease inhibitor taken twice daily.
• ABT-378 was combined with ritonavir, d4T, and 3TC in treatment-naive persons.
• 89% achieved an HIV RNA viral load less than 50 copies/mL.

ABT-378 is a second-generation protease inhibitor from Abbott Laboratories that has demonstrated very high potency when combined with small doses of ritonavir (see BETA, October 1998). The trough (lowest) level of ABT-378 in the blood is the highest of any tolerable double protease inhibitor combination to date. Trough drug levels are associated with potency and resistance potential. ABT-378 and ritonavir are taken twice daily without food restrictions.

Updated interim results were presented by Robert Murphy, MD. In the current study, HIV positive persons without prior anti-HIV therapy were randomized to take ABT-378 at a dose of either 200 mg or 400 mg daily. This was combined with 100-200 mg of ritonavir and standard doses of d4T and 3TC. A total of 101 persons were enrolled. The median baseline HIV RNA viral load was 4.9 log copies/mL and CD4 cell counts were 313-424 cells/mm³.

After 20-24 weeks, 93-96% of participants had an HIV RNA viral load less than the limit of quantitation (400 copies/mL). An ultrasensitive viral load test performed at 24 weeks for 27 persons indicated that 89% had a viral load less than 50 copies/mL. CD4 cell counts increased by approximately 150 cells/mm³.

The regimen was safe and relatively well tolerated. The most common side effects were diarrhea (17-38%), weakness (9%), headache (9%), and nausea (9-17%). No one discontinued the study due to side effects. The four persons who withdrew early did so due to either drug addiction, lymphoma, nonadherence, or moving away. Increased cholesterol levels occurred in 10%, while increased triglyceride levels occurred in less than 3%. Five persons experienced increased liver enzyme levels; however, three of these had concurrent hepatitis B or C viral infection.

This study is ongoing. The double protease inhibitor combination of ABT-378 plus ritonavir appears very promising.

Amprenavir (Agenerase)

Amprenavir Blood Levels

• New research on amprenavir helps explain variability in blood drug levels.
• Racial/ethnic differences exist in levels of alpha-1 acid glycoprotein.
• Unless alpha-1 acid glycoprotein levels are measured in drug studies, incorrect dose recommendations may be made.
• No dosage adjustment of amprenavir is necessary.

On April 15 amprenavir became the fifth protease inhibitor to receive FDA approval. Research conducted by its manufacturer, Glaxo Wellcome, partly explains the wide interpersonal variability in drug levels that can occur with protease inhibitors. Several studies have shown that many HIV positive persons who do not achieve an undetectable viral load have drug levels in their blood that are inadequate, even with 100% adherence. One reason for this may be differing concentrations of various proteins in the blood that bind drugs, rendering them temporarily inactive (only free, unbound drug is active). One of those proteins is alpha-1 acid glycoprotein (AAG).

Brian Sadler, PhD, and colleagues measured AAG levels in African-Americans and Caucasians. Both HIV negative persons and HIV positive persons in amprenavir studies were included in the analysis. The researchers found that AAG concentrations in both HIV negative and HIV positive African-Americans was significantly lower than that in Caucasians. They also determined that the AAG concentration is significantly correlated with how fast amprenavir is eliminated from the body. In addition to race, age and body weight were also found to be significant predictors of AAG concentrations in HIV positive persons.

The authors concluded that even though the differences in AAG concentrations between African-Americans and Caucasians can explain different total amprenavir concentrations in HIV positive persons, the free drug concentrations were the same. Therefore, no dose adjustment of amprenavir is necessary. However, the researchers note that without recognizing AAG variations in different races and ethnicities, the elimination measurements of any drug "can yield potentially misleading conclusions and incorrect dosage recommendations."

There were many presentations at CROI on amprenavir in various clinical trials. Many of them were updates of amprenavir studies already reported or underway (see BETA, January 1999). Studies continue to confirm that amprenavir is a very potent protease inhibitor with a somewhat unique resistance profile. In addition, one presentation revealed a very favorable response to amprenavir combination therapy in children. Amprenavir will be the third protease inhibitor to be made in pediatric formulations (a suspension and small 50 mg capsules); the other two are nelfinavir and ritonavir.

Indinavir (Crixivan)

HIV Rebound May Not Indicate Indinavir Resistance

• Most persons who experience HIV viral load rebound while taking indinavir-containing triple therapy do not have virus resistant to the drug.

Several CROI presentations reported on measurement of levels of drug-resistant HIV after viral load rebound. Two presentations specifically measured resistance to indinavir after rebound. Researchers from Merck and Company examined participants in trials 054 and 067. All were taking indinavir plus either efavirenz or AZT/3TC. Specific levels of drug resistance were measured after viral load rebound occurred. Less than 25% of those tested had HIV strains with genetic mutations associated with indinavir resistance. However, over 70% had HIV mutations associated with resistance to efavirenz, AZT, and/or 3TC. The results are not entirely unexpected, due to the fact that only one mutation can lead to resistance to 3TC or efavirenz, while a series of mutations is required for indinavir resistance.

The authors concluded that when an anti-HIV regimen fails, all drugs may not necessarily need to be changed. Resistance testing may indicate that some of the drugs may be included in a subsequent regimen. The results are somewhat limited by the fact that genotypic resistance testing measures the predominant HIV strains present, and may not detect minority populations that are resistant to indinavir. Also, current genetic resistance tests may not detect all mutations associated with resistance.

A similar report authored by Diane Havlir, MD, and colleagues from the University of California at San Diego also indicated a lack of indinavir resistance. This study included 26 persons who experienced HIV viral load rebound while taking indinavir, AZT, and 3TC. Both phenotypic and genotypic resistance tests were performed. Neither genotypic resistance to indinavir nor phenotypic resistance to any protease inhibitor was detected in those persons who had viral load rebound, but resistance to 3TC was common.

The researchers also measured blood levels of indinavir in the participants with viral load rebound, and compared the results to drug levels in a group of ten controls without viral load rebound. Even though there was no significant difference in the mean indinavir levels between the two groups, the percentage of participants with at least one undetectable indinavir measurement was higher in the group with viral load rebound. These findings may indicate a problem with adherence, drug absorption, or metabolism. Since there is significant interpersonal variability in blood levels of protease inhibitors, drug level testing may have a role in ensuring that therapeutic blood drug levels are achieved.

Indinavir Triple Therapy Still Effective after Three Years

Indinavir triple therapy is still effective after three years for 66% of 33 participants.

• 63% had an undetectable viral load (limit of quantitation 50 copies/mL).
• Viral load rebound occurred in 27% (6% were nonadherent; 18% had some baseline genetic resistance).
• Body fat redistribution occurred in 19%.
• Increased triglyceride levels (greater than 750 mg/dL) occurred in 24%.
• Kidney stones occurred in 39%.
• HIV was undetectable in cerebrospinal fluid (CSF) and almost always undetectable in genital fluids of both men and women.
• HIV genes were still detectable in lymph tissue.

The longest follow-up of any protease inhibitor study was presented at CROI in a report authored by Roy Gulick, MD, and colleagues from Cornell University. The 33 participants (6% women, 21% non-Caucasian) in the Merck 035 study who were assigned to the indinavir triple combination arm have been followed in an open-label fashion (see BETA, October 1998, page 46 for earlier trial results). The only prior anti-HIV therapy was AZT. Standard doses of indinavir, AZT, and 3TC were used. After 148 weeks, two-thirds (20 of 30) had an undetectable HIV viral load (68% using tests with a limit of quantitation of 500 copies/mL and 63% using a 50 copies/mL test). One person had not yet reached 148 weeks, while two persons withdrew for reasons unrelated to the study at weeks 8 and 116. None of these three were included in the analysis. The median CD4 cell count increase was 230 cells/mm³.

Nine participants experienced viral load rebound, and seven of these withdrew from the study. One person also withdrew prematurely due to an adverse event (nausea), and three others withdrew for other reasons. Among the nine with viral load rebound, all but one had some baseline genetic resistance to indinavir and two were nonadherent. At least one kidney stone occurred in 39% of participants during the three years of therapy. At least one episode of increased blood triglyceride levels (greater than 750 mg/dL) occurred in 24%, while 2% had a level greater than 1,200 mg/dL. Among the 21 participants who were in active follow-up, four (19%) had body fat redistribution as determined by a physician's physical examination.

The results indicate that a durable response to indinavir triple therapy can persist for at least three years for the two-thirds of participants who achieve undetectable viral loads. The observation that all but one person with viral load rebound had some baseline genetic resistance to indinavir supports the suggestion to conduct resistance testing before starting anti-HIV therapy. The 39% kidney stone rate was much higher than that seen in other studies, and the 19% fat redistribution rate is also noteworthy.

Indinavir Syrup in Development

• Indinavir syrup is being developed for children who cannot swallow capsules.
• Adults who cannot swallow capsules will also benefit.

Second Trial Stops Twice Daily Dosing of Indinavir

• Dose used was 1,200 mg of indinavir twice daily as part of a combination regimen in ACTG 359.
• Higher HIV viral load rebound occurred in the twice daily indinavir arm.
• All participants in that arm were switched to a standard dose of 800 mg of indinavir three times daily.

Indinavir Triple Combination with ddI and d4T Shows Benefits

• Nearly identical improvements are observed after 24 weeks with indinavir/ddI/d4T and indinavir/AZT/3TC.
• The Atlantic Study enrolled 298 anti-HIV therapy-naive participants.

Nelfinavir (Viracept)

Nelfinavir is Safe for HIV Positive Persons with HBV or HCV

• Nelfinavir is safe for HIV positive persons with liver disease associated with hepatitis B or C viral infections.
• Nelfinavir blood level monitoring is recommended.
• Dosing in some participants was decreased to 500 mg twice daily or 250 mg three times daily, with continued anti-HIV benefits.

Twice Daily Nelfinavir Shows Persistent Benefit

• 1,250 mg of nelfinavir twice daily promotes improved adherence.
• A regimen of 1,250 mg of nelfinavir plus 1,200 mg of indinavir twice daily leads to nearly equivalent drug blood levels as with the standard dose of each protease inhibitor alone.

Ritonavir (Norvir)

Ritonavir Monotherapy Decreases Perinatal Transmission

• 86 pregnant women in Thailand took ritonavir for a mean of 19 days.
• The HIV transmission rate from mother to newborn in 74 evaluable participants was 9%, similar to that of the standard ACTG 076 AZT monotherapy regimen.
• Ritonavir was stopped for 12 women (ten had increased liver enzyme levels, one experienced vomiting, diarrhea, and fever, and one could not swallow the capsules).

Saquinavir (Fortovase)

Twice Daily Fortovase

• 1,600 mg of soft-gel saquinavir (Fortovase) twice daily dosing appears effective.
• Improved adherence may occur with twice daily dosing.

Tipranavir

Results Reported for Tipranavir

• Tipranavir is effective against HIV that is resistant to the first four FDA-approved protease inhibitors in vitro.
• The drug is synergistic with delavirdine, ritonavir, or AZT in vitro.

Results of a phase I/II study of tipranavir (PNU-140690), an experimental protease inhibitor from Pharmacia & Upjohn, were presented at a community meeting immediately following CROI. The presenter was William Freimuth, MD, PhD, from Pharmacia & Upjohn. This very promising drug is effective in vitro against HIV strains that are resistant to the first four FDA-approved protease inhibitors. This may be due in part to tipranavir's having a different, non-peptide dihydropyrone structure. Tipranavir is synergistic with either delavirdine, ritonavir, or AZT in vitro.

A total of 24 persons were enrolled in a 24-week, dose-escalation study (protocol 0004). Tipranavir was added to participants' stable double nucleoside analog regimen. The highest dose of the drug (1,500 mg three times daily) led to a reduction in HIV RNA viral load of 1.5-2.0 log copies/mL. The genetic mutations that developed suggest that tipranavir may have a unique resistance profile different from those of the other protease inhibitors.

Tipranavir was well tolerated, with no serious drug-related adverse events. As is common with the protease inhibitors, most adverse events were related to the stomach and intestines, including nausea, vomiting, and diarrhea. Diarrhea was mild to moderate and decreased over time; only one-third of participants required over-the-counter antidiarrheal medication. Other side effects were dizziness and headache.

During the 24 week study period, neither body fat redistribution (including lipodystrophy) nor increases in blood lipid levels were observed. The results indicate that a three-times-daily regimen of 1,200 mg or 1,500 mg of tipranavir leads to drug levels that are much more than sufficient to prevent HIV replication (i.e., a concentration eight to ten times higher than the EC90). As is the case with indinavir, saquinavir, and ABT-378, dosing with ritonavir significantly increases blood levels of tipranavir. This may allow for twice daily dosing.

Several clinical trials and drug interaction studies of tipranavir are being planned. This second-generation protease inhibitor appears quite promising. If the lack of blood lipid and body fat redistribution side effects persists in larger studies, tipranavir could be a very welcome new protease inhibitor.

Nevirapine (Viramune)

Nevirapine/ddI/d4T and Indinavir/ddI/d4T

• Either nevirapine or indinavir, when combined with d4T/ddI, have benefits nearly equivalent to those of a standard triple regimen of indinavir/AZT/3TC.

Interim results of the Atlantic Study were presented by Christine Katlama, MD, from France. This trial compared three different three-drug combinations: ddI/d4T/nevirapine (group 1), ddI/d4T/indinavir (group 2), and ddI/d4T/3TC (group 3). All 234 participants (20% women) had no prior anti-HIV therapy. The baseline HIV RNA viral load was 4.2 log copies/mL. Results after 24 weeks were presented.

The percentages of participants in groups 1, 2, and 3 who achieved an undetectable HIV viral load (limit of quantitation 500 copies/mL) were, respectively, 69%, 78%, and 71% using an intent-to-treat analysis. Using a more sensitive viral load assay with a lower limit of quantitation of 50 copies/mL, 67%, 71%, and 56% of participants in the three groups, respectively, achieved an undetectable viral load. CD4 cell count increases were approximately 125 cells/mm³ in each of the three groups. The number of persons who withdrew from the study in the three arms were, respectively, five (5), 12, and 11.

Common side effects in all groups were gastrointestinal symptoms, foot/hand numbness, and weakness. Some symptoms could have been due to d4T and/or ddI. As anticipated, participants in group 1 commonly experienced a rash due to nevirapine (22%), whereas participants in group 2 had painful kidney stones more often than in previous indinavir studies (30%). The percentages who withdrew from the study in groups 1, 2, and 3, were, respectively, 7%, 15%, and 13%. The percentages who withdrew due to adverse events, were, respectively, 4%, 3%, and 5%. In group 1, 12% switched to a different regimen because of rash. In group 2, 1% switched due to a kidney stone. Participants in group 3 were not offered the option to switch. There was one death in group 3 due to pulmonary tuberculosis.

Interim results of the Atlantic Study indicate that either nevirapine or indinavir, when combined with d4T/ddI, have benefits nearly equivalent to those of a standard triple regimen of indinavir/AZT/3TC. The study also indicated that d4T/ddI is a good backbone of nucleoside analog drugs. There was a trend towards better efficacy if the third drug was either a protease inhibitor (indinavir) or an NNRTI (nevirapine).

However, even when a third nucleoside analog was added to the backbone, benefits were seen; the triple nucleoside analog arm demonstrated benefits similar to those of another triple nucleoside analog combination--abacavir (Ziagen)/AZT/3TC--used in another major study. As measured by premature withdrawal, the nevirapine triple combination arm fared the best; the other two arms had over twice as many withdrawals. Lastly, the two different protease-sparing regimens showed good benefits, similar to those of an indinavir-containing triple regimen. This study is ongoing with an anticipated follow-up time of 144 weeks.

Delavirdine (Rescriptor)

Delavirdine Triple and Quadruple Combinations Show Excellent Potency

• Delavirdine combination demonstrates decreased HIV disease progression.
• Delavirdine has a very low rate of blood lipid increases and body fat redistribution.
• New 200 mg tablet will decrease daily pill burden by 50%, and new twice daily dosing option should improve adherence. Availability is expected by September 1999.
• Delavirdine combination for children shows benefits in early research.
• Delavirdine-resistant HIV is still sensitive to efavirenz.
• Adefovir significantly decreases delavirdine levels; the two drugs should not be combined.

Several presentations at CROI indicated that delavirdine has much greater potency than previously believed. One presentation was the second study to date to show that a delavirdine-containing triple combination has benefits nearly identical to those of a standard indinavir-containing triple combination. Another study revealed that the four-drug combination of delavirdine/indinavir/AZT/3TC led to 100% undetectable viral load levels using an as-treated analysis. Data tabulated from an early delavirdine study indicates a significantly decreased progression of HIV disease. Due to its lack of serious side effects, a pending new double-strength tablet formulation, and potential twice daily dosing, delavirdine is a very attractive therapy.

Among the highlights presented in Chicago, after 24 weeks of delavirdine/AZT/3TC therapy in treatment-naive participants, 64% had an undetectable HIV RNA viral load (limit of quantitation 40 copies/mL) in an intent-to-treat analysis, and a CD4 cell count increase of over 100 cells/mm³. These results are similar to those of other protease inhibitor-based and NNRTI-based triple combination regimens. This is the second placebo-controlled, protease-sparing study of treatment-naive participants using delavirdine/AZT/3TC that has shown similar benefits.

Interim results of a study using a quadruple regimen of delavirdine/indinavir/AZT/3TC in treatment-naive participants indicated that 100% of nine participants who reached 32 weeks and 100% of three who reached 48 weeks had an undetectable HIV viral load (limit of quantitation 40 copies/mL). CD4 cell counts increased by more than 100 cells/mm³. However, by 24 weeks, 27% of this arm had discontinued treatment for reasons not stated. Common side effects were nausea, vomiting, rash, and headache. Standard dosing for delavirdine, AZT, and 3TC were used, along with a decreased indinavir dose of 600 mg every eight hours.

At 32 weeks, 75% of 13 participants in a control arm receiving indinavir/AZT/3TC had an undetectable viral load (limit of quantitation 40 copies/mL), as did all of the five who completed 48 weeks. This arm had a similar CD4 cell count increase at 32 weeks, yet more than a 250 cells/mm³ increase at 48 weeks. Two other arms in this trial (indinavir/delavirdine/AZT and indinavir/delavirdine/3TC) also fared well. The interim results of this study help to confirm the value of a decreased 600 mg indinavir dose when combined with delavirdine. This trial will continue for a total of 96 weeks.

The final results of an early European/Australian trial of delavirdine plus AZT revealed that a significantly decreased percentage of participants developed a new AIDS-defining event or died (16%) compared to those receiving AZT monotherapy (23%) after one year. While either treatment arm is considered substandard care in 1999, this is the first report of a delavirdine study showing decreased HIV progression.

In analyzing delavirdine studies for rates of increased blood lipid levels and body fat redistribution for the European equivalent of the FDA, Freimuth indicated that Pharmacia & Upjohn has not found a significant causal relationship between the drug and these side effects. Researchers planned to report these findings at the Third International Conference on Nutrition and HIV Infection in late April.

Pharmacia & Upjohn has developed a new 200 mg delavirdine tablet; the current tablet is 100 mg. Approval is anticipated by September 1999. The new tablet will decrease the daily delavirdine pill burden from 12 to six. One 200 mg tablet has demonstrated bioequivalence to two 100 mg tablets.

While cross-resistance among the first three NNRTIs has been assumed, one presentation at CROI suggested that this does not necessarily occur. HIV strains that were resistant to delavirdine were, surprisingly, still sensitive to efavirenz in vitro. The 22 delavirdine-resistant HIV strains also retained sensitivity to an experimental third-generation NNRTI called PNU-142721. The HIV isolates also were sensitive to tipranavir (PNU-140690), an experimental protease inhibitor. If these results are upheld in clinical trials, a case could be made for using delavirdine first, so that if viral load rebound occurs, efavirenz would still be an option.

A six-arm trial, ACTG 359, revealed that adefovir unexpectedly decreased delavirdine drug levels by approximately half. Therefore, delavirdine should not be combined with adefovir.

It is clear that delavirdine combination therapy has earned a place among its peers as having significant potency and potential as an antiretroviral therapy. Its usefulness for treatment-naive and treatment-experienced persons will be confirmed in future clinical studies and in final results of ongoing studies.

Efavirenz (Sustiva)

Efavirenz plus AZT/3TC Shows Sustained Benefits up to 48 Weeks

• Benefits were greater in the efavirenz arm than in the standard indinavir/AZT/3TC arm.
• Discontinuation rate in efavirenz arm was lower than in the indinavir/AZT/3TC arm.
• Increases in HDL ("good") cholesterol occurred at 24 weeks.
• Efavirenz may be useful for HIV positive persons with liver disease.
• Resistance was associated with a K103N mutation.

Additional follow-up of DMP study 006 indicates that the protease-sparing combination of efavirenz/AZT/3TC continues to show potency after one year and to demonstrate a higher rate of undetectable HIV RNA viral load than either a standard indinavir/AZT/3TC combination or an efavirenz/indinavir combination (see BETA, January 1999, page 48). The efavirenz combination requires only five pills daily when Combivir (AZT/3TC) is used. Efavirenz is taken as three capsules once daily without food restrictions or fluid requirements.

Using an intent-to-treat analysis, 71% of participants taking efavirenz/AZT/3TC achieved an undetectable viral load (limit of quantitation 400 copies/mL), compared to 54% of those taking efavirenz/indinavir and 48% of those taking indinavir/AZT/3TC. When using an ultrasensitive viral load test with a limit of quantitation of 50 copies/mL, the undetectable percentages for the three arms were, respectively, 65%, 48%, and 44%. The efavirenz triple therapy arm continued to perform statistically better than the other two arms regardless of baseline HIV viral load levels. For the subset of participants with a baseline viral load greater than 100,000 copies/mL, the percentages in each arm with an undetectable viral load using the ultrasensitive assay were, respectively, 66%, 35%, and 34%. All results were statistically significant. CD4 cell counts increased by 175-200 cells/mm³ in all three arms.

Premature discontinuation rates in the three arms were, respectively, 25%, 35%, and 42%. Premature discontinuation rates due to adverse events were 6%, 6%, and 19%. Adverse events included rash, mental symptoms (dizziness, impaired concentration, headache, insomnia, fatigue, abnormal dreams), and nausea/vomiting in the efavirenz arm; adverse events in the indinavir arm included kidney pain, nausea/vomiting, and fatigue. There were no severe or life-threatening rashes in the efavirenz arm. Rashes and mental symptoms tended to decrease over time.

Both the efavirenz triple combination and the indinavir triple combination arms had nearly equivalent increases in non-fasting cholesterol levels after 24 weeks (approximately a 30 mg/dL increase). Since such cholesterol changes have not been reported with either AZT or 3TC, indinavir and efavirenz are the likely culprits. This is supported by the higher additive cholesterol level that was observed in the indinavir/efavirenz arm (approximately a 60 mg/dL increase). Also of interest was an increase in HDL ("good") cholesterol in both efavirenz-containing arms (approximately 10 mg/dL after 24 weeks). The indinavir triple therapy arm experienced an HDL cholesterol increase of only 4 mg/dL. Results were statistically significant. Since blood lipid measurements were not done in a fasting state, there are no data regarding triglyceride or LDL ("bad") cholesterol levels.

Efavirenz Suspension Being Developed for Children

• Efavirenz is generally well tolerated by children.

Abacavir (Ziagen)

48-Week Follow-Up of Abacavir/AZT/3TC Shows Continued Benefit

• CNA study 3003 included 87 treatment-naive participants (18% women, 51% non-Caucasian).
• Another 86 participants were randomized to AZT/3TC for 16 weeks, then allowed to add open-label abacavir (not included in analysis).
• After 48 weeks, using an intent-to-treat analysis, HIV RNA viral load was undetectable in 61% using a test with a limit of quantitation of 400 copies/mL and in 56% using a 50 copies/mL test.
• CD4 cell counts increased a mean of 150 cells/mm³.
• Side effects in the first four weeks included nausea (47%), fatigue (34%), headache (31%), vomiting (16%), and diarrhea (12%); rates decreased after four weeks.
• A life-threatening abacavir hypersensitivity reaction (fever, rash, aches, and gastrointestinal symptoms) occurred in 2%.
• 25% withdrew from the study prematurely (6% due to an adverse event).
• The study involved a simple regimen of two pills twice daily when the Combivir (AZT/3TC) pill was used.
• Regimen has no food restrictions or fluid requirements.

Abacavir Triple Therapy as Effective as Indinavir Triple Therapy at 24 Weeks

• CNA study 3005 included 562 treatment-naive participants (13% women).
• Study regimens included Combivir (AZT/3TC) plus either abacavir or indinavir.
• After 24 weeks, HIV viral load was undetectable in 65% of both arms (limit of quantitation 400 copies/mL).
• After 16 weeks, 45% of abacavir arm and 42% of indinavir arm had undetectable viral loads using a test with a limit of quantitation of 50 copies/mL.
• Both arms were equally beneficial for participants with either high or low viral loads.
• CD4 cell counts increased approximately 105 cells/mm³ in both arms.
• Fourteen to fifteen percent in each arm withdrew due to side effects, including nausea (5-6%), nausea and vomiting (3-4%), fatigue (3%), rash (2-3%), and fever (5% in abacavir arm; less than 1% in indinavir arm).
• Moderate to severe blood test abnormalities occurred in less than 5% of each arm, including increased liver enzymes, pancreas enzyme (amylase), bilirubin, muscle enzyme (CPK), and triglycerides, as well as low white cell counts.
• Cholesterol increased 5 mg/dL in the abacavir arm and 20 mg/dL in the indinavir arm.
• Body fat redistribution including lipodystrophy was not reported.
• A life-threatening abacavir hypersensitivity reaction occurred in 5% of participants in the abacavir arm; there was one death after abacavir was restarted.
• The authors concluded that abacavir and indinavir triple combinations are nearly equivalent up to 24 weeks, except for hypersensitivity reaction in the abacavir arm and greater increases in cholesterol in the indinavir arm.

d4T (Zerit)

Two Studies Confirm d4T Penetrates Cerebrospinal Fluid (CSF)

• HIV RNA viral load decreases in the CSF.

ddI (Videx)

ddI plus d4T is Confirmed as Another Nucleoside Analog "Backbone"

• ddI/d4T used in combination with either indinavir, nevirapine, or 3TC shows benefits.

At this point in the HIV/AIDS epidemic, AZT/3TC has been the most commonly used treatment "backbone" to which a third drug is added. The Atlantic Study was designed in part to determine whether another nucleoside analog combination--ddI/d4T--could also be effective. The results indicated that ddI/d4T is a good nucleoside analog backbone. There was a trend towards better efficacy if the third drug was either a protease inhibitor (indinavir) or an NNRTI (nevirapine), but even when a third nucleoside analog (3TC) was added, benefits were seen.

Methadone Decreases ddI Blood Levels by 60%

• Dose of ddI will need to be increased in persons taking methadone; methadone dose remains the same.

Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee of the San Francisco AIDS Foundation since 1987.

Page last updated 1 June 1999