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Selected Highlights from the 12th World AIDS Conference</b>
Harvey S. Bartnof, M.D.
October 11, 1998

Efavirenz (Sustiva)

Efavirenz Triple Therapy

  • Efavirenz triple combination therapy has advantages over indinavir triple combination.
  • Both efficacy and tolerability are better at 24 weeks.
  • Other efavirenz-containing combinations demonstrate efficacy.
  • Efavirenz combinations effectively penetrate the brain.

Perhaps the most impressive treatment results from the conference were 24-week interim data from study DMP266-006, an ongoing Phase III, randomized, open-label study comparing three regimens: 1) efavirenz/AZT/3TC, 2) efavirenz/indinavir, and 3) indinavir/AZT/3TC. Efavirenz (formerly DMP-266) is a potent, long-acting non-nucleoside reverse transcriptase inhibitor (NNRTI) that may be taken once daily with or without food. [Editor's note: the FDA approved efavirenz on September 18, 1998.]

A total of 450 patients (14% women, 40% racial/ethnic minorities) have been randomized so far. Participants had no previous use of protease inhibitors, NNRTIs, or 3TC (85% had no prior anti-HIV therapy of any kind), a CD4 count of at least 50 cells/mm3, and a viral load of at least 10,000 copies/mL.

Using an ultrasensitive viral load assay (limit 50 copies/mL), 59% of those in arm 1, 47% in arm 2, and 44% in arm 3 achieved an undetectable viral load. The difference between arm 1 and arm 3 was statistically significant. CD4 count increases were approximately equal in all three arms (115-134 cells/mm3).

The discontinuation rates were lower in the two efavirenz arms (21%, 24%, and 38%, respectively). Significantly more rash (10-15% vs 5%), dizziness (5-9% vs 1%), and insomnia (5% vs 1%) were seen in the efavirenz arms, compared with arm 3. More nausea (22% vs 10%), vomiting (13% vs 5%) and kidney pain (10% versus none) were seen in the 3-drug indinavir arm, compared with the 3-drug efavirenz arm. Other common side effects in the efavirenz arms included fatigue, impaired concentration, headache, and indigestion. Approximately 1-2% of both efavirenz arms discontinued due to rash.

In a substudy analyses of eight patients taking the efavirenz triple or double combinations for a mean of 26 weeks, HIV viral load was undetectable (limit 400 copies/mL) in the cerebrospinal fluid.

The authors conclude that, after 24 weeks, the triple combination of efavirenz/AZT/3TC has superior efficacy, superior tolerability, and easier dosing (twice daily) than indinavir/AZT/3TC, spares protease inhibitor therapy, and represents a new option for the initial treatment of HIV infection.

This intriguing study is ongoing and will enroll a total of 1,200 patients. It is possible that the superior benefits of efavirenz triple therapy will not be sustained after longer follow-up. Even if this were the case, however, durability of HIV suppression has been correlated with the speed of viral load reduction, which still favors efavirenz.

A related, Phase III study (DMP 266-020) compared a 4-drug arm (efavirenz/indinavir plus two nucleoside analogs) to a standard indinavir triple therapy arm. One hundred eighty-four patients (20% women) were enrolled at the time of the report. As in the study above, prior protease inhibitor and NNRTI use was not permitted, but all participants had received at least eight weeks of nucleoside analog therapy. Using an ultrasensitive viral load test (limit 50 copies/mL), 36% of those taking indinavir triple therapy and 54% taking 4-drug therapy achieved an undetectable viral load after 24 weeks. Discontinuations due to adverse events were 11% in the 4-drug arm and 7% in the 3-drug arm. Significantly different adverse side effects were diarrhea (12% in the 4 drug-arm vs 3% in the 3-drug-arm) and dizziness (8% and none, respectively). Rash occurred in 8% and 6% of each arm, respectively.

The authors concluded that the 4-drug regimen of efavirenz/indinavir plus two nucleoside analogs has significant benefits over the same regimen without efavirenz in people who have received prior nucleoside analog treatment.

Finally, another Phase II study, DMP 266-005, compared several doses (200-600 mg) of efavirenz in combination with AZT/3TC in 137 antiretroviral therapy-naive patients. The interim results after 36 weeks were somewhat similar to those after 24 weeks in the 006 study above. The 600 mg dose was found to be most effective. However, the rates of certain side effects were higher in the current study. These included rash (12%), stomach/intestine pain (13%), indigestion (14%), insomnia (17%), diarrhea (24%), headache (24%), fatigue (26%), dizziness (28%), and nausea (38%).

Fessel, W.J. and others. A phase III, double-blind, placebo-controlled, multicenter study to determine the effectiveness and tolerability of the combination of efavirenz and indinavir versus indinavir in HIV-1 infected patients receiving nucleoside analogue therapy at 24 weeks. Abstract 22343.

Haas, D.W. and others. A phase II, double-blind, placebo-controlled, dose ranging study to assess the antiretroviral activity and safety of efavirenz in combination with open-label zidovudine and lamivudine at 36 weeks. Abstract 22334.

Staszewski, S. and others. A phase III, multicenter randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine (ZDV) + lamivudine (3TC) , versus IDV+ZDV+3TC at 24 weeks. Abstract 130/22336.

Tashima, K.T. and others. Cerebrospinal fluid HIV-1 RNA levels and efavirenz concentrations in patients enrolled in clinical trials. Abstract 32202.

Efavirenz plus Nelfinavir Effective at 16 Weeks

An interim 16-week analysis of study ACTG 364 was presented by Mary Albrecht, MD, from Beth Israel-Deaconess Medical Center in Boston. This Phase II, randomized study is a roll-over from several studies of patients with prior nucleoside analog therapy. A total of 194 patients (10% women) were randomized into one of three arms: 1) efavirenz/nelfinavir plus two nucleoside analogs, 2) efavirenz plus two nucleoside analogs, or 3) nelfinavir plus two nucleoside analogs. Mean baseline viral load was 7,625 copies/mL and mean baseline CD4 count was 388 cells/mm3.

At 16 weeks, 81% in the 4-drug arm, 69% in arm 2, and 64% in arm 3 had achieved an undetectable viral load (limit 400 copies/mL). The results for the 4-drug and the nelfinavir 3-drug arm were significantly different. Moderate or severe adverse effects occurred in 13%, 6%, and 11%, respectively. More favorable outcomes were correlated with fewer baseline HIV gene resistance mutations.

The authors concluded that the 4-drug combination led to a greater interim viral load reduction than either 3-drug arm, and that it was well tolerated in this extensively nucleoside analog-pretreated group. The study is ongoing until 48 weeks of follow-up.

Other trials have also shown good results for the efavirenz/nelfinavir combination.

This combination (with or without additional drugs) may achieve the level of strength and durability that efavirenz/indinavir has shown. A modification to a twice daily nelfinavir dose would be of greater interest, due to easier adherence.

Albrecht, M. and others. ACTG 364: virologic efficacy of nelfinavir and/or efavirenz in combination with new nucleoside analogs in nucleoside experienced subjects. Abstract 125/12203.

Eyster, E. and others. Initial effectiveness and tolerability of nelfinavir in combination with efavirenz in antiretroviral therapy naive or nucleoside analogue experienced HIV-1 infected patients: characterization in a phase II, open-label, multicenter study at 16 weeks. Abstract 22386.

Efavirenz/Indinavir: Continued Benefits up to 72 Weeks

Researchers reported additional data from a study of efavirenz/indinavir. Results are now available for people who have been treated for 72 weeks. The 101 patients (14% women) were naive to protease inhibitors and NNRTIs; 71% had prior experience with nucleoside analogs. At 72 weeks, 73% have undetectable HIV RNA viral load (limit 400 copies/mL). The mean CD4 count increase was 243 cells/mm3. Moderate or severe adverse events were experienced by 5-9%, including abdominal pain, rash, blood in the urine, diarrhea, nausea, headache, and increased liver enzymes; no severe rashes were seen. Just 3% of participants withdrew prematurely due to adverse events. This combination represents an alternative for those who cannot be treated with nucleoside analogs.

Havlir, D. and others. Sixteen-week follow-up of indinavir sulfate administered Q8 hours versus Q12 hours in combination with efavirenz. Abstract 12290.

Riddler, S. and others. Durable clinical anti-HIV-1 activity (72 weeks) and tolerability for efavirenz (DMP 266) in combination with indinavir. Abstract 12359.

Efavirenz plus Rifampin: Hold Off for Now

Drug levels of rifampin, an anti-tuberculosis drug, are not significantly altered by the co-administration of efavirenz. However, due to rifampin's induction of the CP450 liver enzyme system, co-administration with efavirenz led to a mean 26% reduction in efavirenz blood concentration ("area under the curve"). While this would suggest a need to increase the dosage of efavirenz, there are currently insufficient safety data to recommend a daily dose greater than 600 mg. Therefore, until there are more safety data, hold off on combining these two drugs for now.

Benedek, I.H. and others. Pharmacokinetic interaction between efavirenz and rifampin in healthy volunteers. Abstract 42280.

Abacavir (Ziagen)

Abacavir Triple Therapy Shows Benefits at 16 Weeks

  • Triple combination of abacavir/AZT/3TC was used.
  • Efficacy and tolerability were similar to standard 3-drug therapies.
  • Simple dosing regimen includes two pills twice daily, without food restrictions.
  • The abacavir triple combination also shows efficacy in children.

Margaret Fischl, MD, from the University of Miami, presented 16-week interim data from study CNA3003. This trial compared abacavir/AZT/3TC to AZT/3TC alone in patients without prior anti-HIV therapy. Abacavir (formerly 1592) is an experimental guanosine analog. The dose is 300 mg twice daily, and the drugs comes in a liquid formulation for children. This Phase III study was randomized and double-blind. Entry criteria included a CD4 count of at least 110 cells/mm3. There was no minimum viral load threshold, and all participants had no prior anti-HIV therapy.

A total of 173 patients (24% women; 46% racial/ethnic minorities) were enrolled, with a median baseline viral load was 4.6 copies/mL and a median baseline CD4 count of 427-473 cells/mm3.

Eighty-six percent of enrollees have reached the 16-week point and were evaluated. Using an ultrasensitive viral load assay (limit 50 copies/mL), 54% of the triple therapy arm and 15% of the double therapy arm had undetectable HIV viral loads. Among those with a baseline viral load greater than 100,000 copies/mL, only 33% achieved undetectability. However, among those with a baseline viral load less than 10,000 copies/mL, 62% achieved undetectability. The mean CD4 count increase was approximately 85 cells/mm3 in both arms.

Adverse events were common in both groups, but they did not usually cause participants to withdraw from study. For the 3-drug and 2-drug groups, respectively, the following were common adverse side effects: nausea (47%, 41%), fatigue and malaise (34%, 25%), headache (31%, 20%), vomiting (16%, 11%), diarrhea (12%, 11%), appetite loss (11%, 10%), indigestion (7%, 7%), stomach/intestine pain (4%, 7%), dizziness (5%, 6%), sleep problems including insomnia (7%, 5%), and muscle or bone pain (7%, 5%). An abacavir hypersensitivity reaction occurred in 2 of 87 patients (2.3%). Severe laboratory abnormalities occurred in 14% of those on the 3-drug arm and 12% of those on the 2-drug arm. The only adverse events that were significantly more frequent in the abacavir-containing arm were hypersensitivity reaction, nausea, fatigue, headache, vomiting, and possibly sleep problems. Abacavir did not significantly increase the rate of abnormal laboratory tests. In the 3-drug group, three patients withdrew due to adverse events (two due to abacavir hypersensitivity reaction and one due to headache, vomiting, and low white cell count).

The authors concluded that the 3-drug regimen of abacavir/AZT/3TC is a potent triple therapy regimen for HIV-infected patients without prior anti-HIV therapy. A simple dosing regimen allows for two pills to be taken twice daily (using the AZT/3TC Combivir pill). Despite the relatively high rates of adverse events, the abacavir-containing regimen was nearly as well-tolerated as the double combination of AZT plus 3TC. It appears that this 3-drug regimen may be on a par with standard triple combinations. If this remains the case after longer follow-up, this will be the first example of effective triple combination therapy in which all three drugs are from the same class. This regimen has the advantage of deferring use of the other two currently used classes of anti-HIV therapies. Abacavir also has the advantage of having no known interactions with other drugs. The study will be ongoing through 48 weeks.

A poster by Schlomo Staszewski, MD, described a related open-label study that demonstrated continued benefits for the triple combination of abacavir/AZT/3TC for 48-72 weeks in 60 patients (none with prior anti-HIV therapy). After 72 weeks of therapy, 50% had an undetectable viral load (limit 50 copies/mL). This is somewhat lower than the 54% undetectability level achieved after 16 weeks in the study above; however, the current study used abacavir monotherapy for the first 4-24 weeks (a practice that would not take place today). The median CD4 count increase was 150 cells/mm3. The most common adverse experiences were similar to those seen in the 3-drug arm above: nausea or vomiting (41%), fatigue (18%), headache (16%), muscle pain (11%), stomach/intestine pain (12%), sleep problems (7%), and skin rash (7%).

Fischl, M. and others. Safety and activity of abacavir (1592) with 3TC/ZDV in antiretroviral naive subjects. Abstract 127/12230.

Kelleher, D. and others. Activity of abacavir (1592) combined with protease inhibitors in therapy-naive subjects. Abstract 12210.

Price, R.W. and others. Pharmacokinetics of abacavir (1592U89) in cerebrospinal fluid (CSF) using multiple lumbar punctures in few subjects and sparse sampling techniques. Abstract 42271.

Staszewski, S. and others. Abacavir combination therapy in HIV-1 infected adults: durability to 72 weeks. Abstract 12212.

Van Dyke, R. and others. Antiretroviral activity and safety of abacavir (1592) with 3TC/AZT in therapy-experienced children. Abstract 128/12255.

Abacavir Side Effects

  • Abacavir side effects were quantified in a meta-analysis of 2,367 patients.
  • Most common adverse events are nausea, vomiting, fatigue, malaise, headache, and rash.
  • Most side effects are mild or moderate, temporary, and usually do not lead to drug discontinuation.
  • Rate of life-threatening hypersensitivity reaction is 2.8%.

Seth Harrington, MD, from GlaxoWellcome authored a poster that quantified the side effects of abacavir. A meta-analysis of the nine clinical trials using abacavir included 690 patients. This was combined with data from the first 1,677 patients taking the drug on open-label basis, for a total of 2,367 patients. No significant toxicity was seen affecting the bone marrow, kidney, liver, or pancreas.

The abacavir hypersensitivity reaction was measured to occur at a rate of 2.8%. The following constellation of symptoms occurred in definite and probable cases, respectively: fever (70%, 80%), rash (55%, 75%), nausea (30%, 45%), mouth or throat sores (20%, 25%), inflammation of the white of the eye (5%, 8%), respiratory symptoms (10%, 20%), and muscle aches (8%, 20%). It is not necessary to have all symptoms to have the reaction. The reaction occurs a mean of 11 days after starting abacavir. Almost all reported cases have occurred within the first six weeks after starting the drug. Since death has occurred when a person is rechallenged with abacavir after the initial hypersensitivity reaction, anyone taking abacavir who notices any of the above symptoms should immediately contact their physician or report to the closest emergency room.

A new drug application (NDA) for abacavir was submitted to the FDA by GlaxoWellcome in June. Fast track approval is likely before the end of 1998. Until approved, it is available under expanded access; physicians may call 1-800-501-4672.

Harrington, S. and others. Safety and tolerance of abacavir (1592) alone and in combination therapy for HIV-1 infection. Abstract 12353.

Abacavir for AIDS Dementia Complex

  • In patients with AIDS dementia, abacavir dose was increased to 600 mg twice daily.
  • No significant improvements in dementia were measured.

The potential use of double dose abacavir for AIDS dementia complex was described in separate presentations by Bruce Brew, MD and Justin McArthur, MD. The presentations examined separate aspects of Study CNA3001, a 12-week trial with 99 participants (2% women). Abacavir (600 mg twice daily) was added to the participants' existing anti-HIV therapy. A control group did not receive abacavir. Abacavir has been shown to have an excellent penetration into the cerebrospinal fluid (CSF). Dementia measurements included verbal memory and fluency, reaction time, and several psychomotor tests.

The results showed no significant changes in dementia scores comparing the two arms. However, the baseline rate of resistance to nucleoside reverse transcriptase inhibitors was over 90% in the patients in this study. This likely limited the potential benefits of abacavir. Despite the lack of significance, those in the abacavir arm did have a CSF viral load reduction of 0.64 log copies/mL, compared to an increase of 0.25 log copies/mL in the control arm. In the abacavir arm, 46% achieved an undetectable blood viral load (limit 400 copies/mL), compared to 13% in the control arm; this difference was highly significant. The authors found that HIV resistance patterns were different for 62% of the participants when comparing CSF and blood. This finding provides additional evidence that HIV may evolve differently in various body compartments.

Brew, B.J. and others. Safety and efficacy of abacavir (1592) in AIDS dementia complex (Study CNAB 3001). Abstract 561/32192.

Lanier, R. and others. Viral resistance and viral load response to abacavir (1592) in an AIDS dementia complex trial (CNA3001). Abstract 32293.

Amprenavir (Agenerase)

Abacavir plus Amprenavir Demonstrates High Potency

  • At 48 weeks, viral load reduction was 4 log copies/mL.
  • Viral load was undetectable in 85% (limit 50 copies/mL) and 65% (limit 5 copies/mL), depending on test used.
  • CD4 counts increased by over 200 cells/mm3; majority are naive T-cells.
  • CD4 cell percentage became normal in lymph nodes.

Another set of impressive results was presented by Pierre-Alexandre Bart, MD, and colleagues from the AIDS Immunopathogenesis Laboratory in Lausanne, Switzerland. The Phase II, observational, open-label study included 41 treatment-naive patients (22% women). Entry criteria included a CD4 count of at least 400 cells/mm3, and a viral load greater than 5,000 copies/mL. Mean baseline viral load was 4.42 log copies/mL and mean baseline CD4 count was 756 cells/mm3.

The study examined the effects of two experimental drugs, abacavir plus amprenavir. Amprenavir (Agenerase, formerly 141W94 and VX-478) is a new protease inhibitor drug from Vertex Pharmaceuticals and GlaxoWellcome which will likely be approved by the FDA by early-to-mid 1999. Doses used were 300 mg twice daily abacavir and 1,200 mg twice daily amprenavir.

Only nine patients have reached the 48 week mark and been evaluated. While the number of patients is quite small, the virological endpoints rank among the top few ever reported. Viral load was undetectable in 85% using a test with a limit of detection of 50 copies/mL, and 65% using an even more sensitive test (limit 5 copies/mL). The CD4 count increase of over 200 cells/mm3 included 130 cells/mm3 that were of the naive type and 70 cells/mm3 of the memory type. This finding is consistent with a partial restoration of a more normal immune system. Also in support of this was the return of a normal CD4 percentage in the lymph nodes. It is quite likely that the extremely impressive virological endpoints in this study may be in part due to the participants' good baseline immune status, specifically the near-normal baseline mean CD4 count.

Side effects were significant and decreased with time. They included nausea, vomiting, diarrhea, indigestion, fatigue, headache, numbness, and rash. The only two subjects who discontinued did so due to rash and fever, suggesting a hypersensitivity reaction. It appears that either drug can cause a rash. Mean blood fat levels increased, undoubtedly due to the amprenavir. Triglycerides were increased, but tended to return toward normal over time; cholesterol increased significantly and tended to remain elevated. Other reasons for early discontinuation included pancreatitis (inflammation of the pancreas), Kaposi’s sarcoma, and "psychological reasons."

The study will continue for a total of 72 weeks. Abacavir and amprenavir are also being studied with other antiretroviral agents in other studies.

Bart, P.-A. and others. Combination abacavir (1592)/amprenavir (141W94) therapy in HIV-1 infected antiretroviral-naive subjects with CD4 counts >400 cells/´┐ŻL and viral load >5,000 copies/mL. Abstract 286/12204.

Amprenavir/AZT/3TC Shows Benefits through 60 Weeks

  • HIV viral loads decreased and CD4 cell count increased significantly.
  • Rate of skin rash was 50% in the highest dose arm; 20% of that arm withdrew from the study early due to rash.
  • One patient had a life-threatening rash, likely due to amprenavir.
  • Resistnce profile of amprenavir differs somewhat from those of the other protease inhibitors.

The 60 week results of study PROA2002 were presented by Richard Haubrich, MD, from the University of California at San Diego. The Phase II, partially blinded study compared different doses of amprenavir when combined with standard doses of AZT and 3TC. The three daily doses of amprenavir were 900 mg, 1,050 mg, and 1,200 mg. The fourth arm received AZT/3TC alone for the first 12 weeks; thereafter, amprenavir was added at 1,050 mg daily. Eighty participants (19% women, 15% racial/ethnic minorities) were enrolled. They had no prior therapy with 3TC or any protease inhibitor, and less than a year of prior ddI or ddC. Mean baseline viral load was 4.75 log copies/mL and mean baseline CD4 count was 365-450 cells/mm3.

At 60 weeks, 86% (6 of 7) in the 1,200 mg arm, 73% (11 of 15) in the 1,050 mg arm, 64% (7 of 11) in the 900 mg arm, and 55% (6 of 11) in the delayed amprenavir arm had attained an undetectable viral load (limit 400 copies/mL). CD4 count increase was 200 cells/mm3 in the 900 mg arm and ranged from 125-140 cells/mm3 in the other three arms. The viral load results were only reported for patients who were still on treatment (an "as-treated" analysis), a somewhat less rigorous statistical analysis.

Adverse events in the first 12 weeks were common, and included nausea (53%), fatigue (29%), headache (28%), intestinal gas (26%), diarrhea (23%), rash (23%), numbness around the mouth (18%), vomiting (15%), stomach/intestine pain (14%), viral respiratory infection (13%), sleep disorder (11%), loss of appetite (10%), and sinus problems (10%). The rate of rash in the 1,200 mg arm was 50%, compared to 15% in the other three arms. Eighty percent of the ten rashes that occurred in the highest dose arm were reported as mild-to-moderate (grade 1 or 2) in severity. However, one patient developed Steven’s Johnson syndrome, a severe life-threatening allergic reaction requiring hospitalization. This syndrome has been reported rarely with other anti-HIV drugs. Severe (grade 3 or 4) laboratory abnormalities included increased liver enzymes (4-6%), increased bilirubin (1%), increased amylase (1%), increased blood sugar (4%), low hemoglobin (1%), low white cell count (4%), and increased blood fats (1%). Four percent of participants withdrew from the study due to nausea and vomiting, 8% due to rash (20% of the 1,200 mg arm), 1% due to anemia, 1% due to "allergy and allergic reaction," 1% due to high triglyceride (fat) levels, 1% due to increased liver enzymes, and 6% due to other adverse events.

The results of the study indicate that the triple combination of amprenavir/AZT/3TC is effective for those who can tolerate the adverse effects. The side effect profile of the combination is problematic, particularly the high rate of rashes in the 1,200 mg arm. Other studies with amprenavir have not yielded such a high rate of rashes. Results of Phase III trials will help to discern the true rate of rash and discontinuation rates associated with amprenavir; GlaxoWellcome currently plans to use the 1,200 mg dose in Phase III studies.

Drug Interactions with Amprenavir

Brian Sadler, PhD, and colleagues from GlaxoWellcome reported on various drug interactions with amprenavir. No dose adjustment is necessary for either drug when amprenavir is co-administered with AZT, 3TC, abacavir, indinavir, nelfinavir, ketoconazole, or clarithromycin. When co-administered with saquinavir, no dosage adjustment is necessary for saquinavir. Possible dose adjustments when co-administered with efavirenz are not currently available pending the outcome of additional studies. The anti-tuberculosis drug rifampin should not be prescribed with amprenavir, due to accelerated rifampin metabolism. The dosage of rifabutin dosage should be reduced when given with amprenavir.

Haubrich, R. and others. Phase 2 study of amprenavir, a novel protease inhibitor, in combination with 3TC/ZDV. Abstract 12321.

Myers, R.E. and others. Unique resistance profile of the protease inhibitor amprenavir (141W94) observed in vitro and in the clinic. 2nd International Workshop on HIV Drug Resistance and Treatment Strategies. Abstract 48.

Sadler, B. and others. Pharmacokinetic drug interactions with amprenavir. Abstract 12389.

Tisdale, M. and others. Genotypic and phenotypic analysis of HIV from subjects on ZDV/3TC/amprenavir combination therapy. Abstract 32312.

Adefovir Dipivoxil (Preveon)

Adefovir Combination Therapy

  • Adefovir combinations demonstrate efficacy to 20 weeks in 66 patients.
  • HIV RNA viral load reductions and CD4 count increased are similar to those seen with indinavir triple combination therapy.
  • Severe laboratory adverse events were seen in 30% of the adefovir arm.
  • Adefovir has a unique resistance profile, and has increased activity against 3TC-resistant HIV strains.

Melanie Thompson, MD, from the AIDS Research Consortium in Atlanta, presented interim 20-week data from an open-label, Phase II, controlled study of adefovir combination therapy. Adefovir dipivoxil (bis-POM PMEA) is an experimental nucleotide analog reverse transcriptase inhibitor that can be taken once daily at 120 mg. It should be used with L-carnitine, an essential amino cid that is decreased when adefovir is taken. In addition to HIV, adefovir also has activity against cytomegalovirus (CMV) and hepatitis B virus.

Study 411 enrolled 164 patients (9% women; 41% racial/ethnic minorities). All were essentially without prior anti-HIV therapy (four weeks or less of nucleoside analog therapy was permitted). The median baseline viral load was 4.6 log copies/mL and the median baseline CD4 count was 401 cells/mm3. The study had five arms: 1) adefovir/indinavir/AZT/3TC, 2) adefovir/indinavir/AZT, 3) adefovir/indinavir/3TC, 4) adefovir/indinavir/d4T, and 5) indinavir/AZT/3TC.

Interim 20-week results were available for the first 85 of 164 enrolled participants. Using a strict definition of completion (an "intent-to-treat" analysis), the percentages in each arm that achieved an undetectable viral load (limit 400 copies/mL) were: 1) 50%, 2) 67%, 3) 71%, 4) 61%, and 5) 63%. Note that the 4-drug arm fared somewhat worse than the other arms, which were fairly equivalent. The study did not have enough participants to allow for statistical significance evaluation. An average of 62% of those in the four adefovir-containing arms achieved undetectability, equivalent to 63% in the control arm. Using a less strict definition of completion (an "on study" analysis that excluded those who withdrew), the percentages that achieved an undetectable viral load were: 1) 80%, 2) 83%, 3) 80%, 4) 79%, and 5) 80%. Median CD4 count increases for the four adefovir arms ranged from 82-109 cells/mm3, compared with an increase of 66 cells/mm3 in the control.

The rates of severe adverse laboratory events (grade 3-4) were somewhat higher in the adefovir-containing arms. A severe increase in liver enzymes occurred in 11% (5 of 44) of those in the adefovir-containing arms, compared with 5% (1 of 19) in the control arm. Increased bilirubin levels were seen in 11% (5 of 44) of those in the adefovir-containing arms and in none of those in the control arm. Severe anemia occurred in 5% of those in the control arm and in no adefovir-treated patients, while severe blood sugar elevations occurred in 5% of adefovir-treated patients and in no control patients. Overall, severe laboratory events were seen in 30% (13 of 44) of those in the adefovir-containing arms, compared to only 16% (3 of 19) of those in the control arm. The percentage not completing 20 weeks of the study was essentially equivalent in the adefovir-containing and control arms (20% and 21%, respectively). However, the early discontinuation rate for the 4-drug adefovir arm was higher at 37%; half the discontinuations were due to adverse events.

While only interim data was reported, the authors concluded that adefovir 120 mg once daily is safe, well-tolerated, and shows anti-HIV activity for 20 weeks. Even though the study was not statistically powered to determine significance, the authors concluded that the combination of adefovir/indinavir plus one or two nucleoside analogs initially appears to reduce HIV viral loads and increase CD4 counts to levels similar to those seen with the standard indinavir/AZT/3TC regimen. This trial is ongoing.

Dr. Thompson stated that another Phase II trial will include 250 patients in three arms. One arm will receive adefovir/indinavir/3TC, a combination that was likely chosen on the basis of a documented increase in the activity of adefovir against HIV strains that have the M184V 3TC-resistance mutation.

Adefovir-Related Kidney Toxicity and Weight Loss

  • Mostly reversible kidney abnormalities occurred in 32% at 48 weeks.
  • Increased liver enzymes occurred in 8-9%.
  • Weight loss averaging six pounds occurred at 48 weeks.
  • All persons taking adefovir should have monthly testing of blood creatinine and electrolyte (salt) levels to monitor kidney function.
  • Adefovir expanded access study is modified to randomize patients to receive either 120 mg or 60 mg.

Results of a study of adefovir in patients with prior anti-HIV therapy were presented by James Kahn, MD, from San Francisco General Hospital. Study 408 was a Phase II/III, randomized, double-blind, placebo controlled study of 442 participants that lasted for 24 weeks, with an additional 24 weeks of open-label follow-up. Adefovir at 120 mg daily or a placebo was added to participants' existing antiretroviral regimen.

A disturbing finding not previously reported was the rate of kidney toxicity. Even though the rate was only 1% at 24 weeks, 32% of participants had evidence of kidney toxicity at 48 weeks. The abnormality, proximal renal tubular dysfunction (PRTD) can lead to abnormal urine filtering and loss of electrolytes (salts) and organic acids. The condition is characterized by increased blood creatinine levels, decreased blood phosphate and bicarbonate levels, and protein and sugar in the urine. All cases of PRTD were classified as mild to moderate, and were at least partially reversible with discontinuation or dose reduction of adefovir. The prevalence of PRTD increased with time; 37% of participants had the condition after 100 weeks of follow-up.

Another disturbing finding was weight loss in the adefovir arm. During the first 24 weeks, body weight decreased by 5.3 pounds in the adefovir arm, compared to no change in the control arm. For those initially assigned to the adefovir arm, weight loss continued through week 32; however, subsequently, there was a slight increase and stabilization of weight. Weight loss occurred primarily in the heaviest patients. The authors are currently conducting other analyses to determine correlates of the weight loss associated with adefovir.

The authors concluded that in patients with substantial prior histories of anti-HIV therapy, 120 mg of daily adefovir can provide some viral load benefits over 48 weeks. The weight loss and reversible kidney toxicity are worrisome adverse effects.

A larger analysis of adefovir adverse effects was reviewed by James Rooney, MD, from Gilead Sciences, the manufacturer of the drug. In seven trials, 3,600 HIV positive patients had taken the drug as of May 31, 1998. However, only 550 of those had taken the drug for longer than six months. The rate of adverse events, including kidney toxicity, in the entire group was actually rather low. Only 4% of the entire group had any serious adverse events. Serious increases in liver enzymes occurred in 2%, and were often related to existing viral hepatitis, substance abuse, and/or other anti-HIV therapies. Serious increases in creatine kinase occurred in 2%. Serious nausea, vomiting, and/or diarrhea were reported in only 1%. Serious kidney toxicity occurred in only 1%, half of which had PRTD. However, for those treated for longer than six months, the rate was 4%. There was an increased risk of developing PRTD in those with high blood pressure, dehydration, and/or sepsis. Of the 79 patients with PRTD, resolution occurred in 73% after a median of 8-12 weeks; of these, 62% experienced resolution after stopping adefovir and 38% had resolution despite continued therapy (presumably at reduced doses).

Rooney explained that, as a result of kidney toxicity, Gilead has changed the protocol for managing patients taking adefovir. All patients taking adefovir should have monthly blood tests of creatinine, phosphorous, and bicarbonate levels. Supplemental tests may be needed for additional electrolyte abnormalities. Dose reduction of adefovir may be necessary.

The adefovir expanded access program has also been modified due to the recognition of kidney toxicity. The program initially included one dose level (120 mg). As of May 27, 1998, patients entering the program will be randomized to receive either 60 mg or 120 mg once daily. To minimize the potential for kidney toxicity, all patients initially randomized to receive 120 mg will have their dose reduced to 60 mg at week 16. Preliminary results of another study (GS-97-417) reveal no significant differences in the benefits of adefovir when comparing the 60 mg and 120 mg doses.

Julie Cherrington, PhD, also from Gilead, presented an interesting sub-analysis correlating the degree of viral load reduction after 24 weeks with baseline resistance mutations. Her analysis showed that for those with baseline 3TC resistance, the mean viral load reduction was significantly greater (0.94 log copies/mL) than the mean reduction for those with no baseline 3TC resistance mutations (0.65 log copies/mL). Furthermore, those having both a baseline resistance mutation to 3TC and high level resistance to AZT had a viral load reduction of 0.51 log copies/mL! Cherrington noted that development of resistance mutations to adefovir was uncommon. Among 100 participants who took adefovir for six months or longer, none developed the K65R mutation and only 2% developed the K70E mutation.

Although adefovir dipivoxil is a nucleotide analog with a unique resistance profile, interim results suggest that it has better efficacy in treatment-naive patients. Triple and quadruple therapy with indinavir plus 1-2 nucleoside analogs appears to have similar efficacy to a standard indinavir regimen. Rates of adverse events, including kidney toxicity and weight loss, will need to be better quantified with additional analyses, longer-term follow-up, and new studies. In the mean time monthly testing for kidney malfunction is a must for those taking adefovir.

Barriere, S. and others. Safety of adefovir dipivoxil in the treatment of HIV infection. Abstract 12386.

Brosgart, C. and others. Serum carnitine levels in AIDS patients with advanced disease from the CPCRA 039 trial. Abstract 60508.

Cherrington, J. and others. Genotypic characterization of HIV-1 isolated from AIDS patients after prolonged therapy with Preveon (adefovir dipivoxil) added to existing regimens. Abstract 60706.

Cherrington, J. The resistance profile of adefovir dipivoxil. New Options for HIV Therapy. Gilead satellite symposium. Geneva, Switzerland, July 1, 1998.

Cherrington, J. and others. Adefovir (PMEA) and PMPA show synergistic or additive inhibition of HIV replication in vitro in combination with other anti-HIV drugs. Abstract 41195.

Kahn, J. Multicenter, randomized, placebo-controlled study of adefovir dipivoxil when added to standard antiretroviral therapy in treatment-experienced patients. New Options for HIV Therapy. Gilead satellite symposium. Geneva, Switzerland, July 1, 1998.

Miller, M. and others. HIV-1 expressing the 3TC-associated M184V mutation in reverse transcriptase show increased sensitivity to adefovir and PMPA as well as decreased replication capacity in vitro. Abstract 41214.

Rooney, D. Adefovir dipivoxil safety update. New Options for HIV Therapy. Gilead satellite symposium. Geneva, Switzerland, July 1, 1998.

Thompson, M. and others. Interim analysis of adefovir dipivoxil as part of a combination regimen in treatment-naive patients. New Options for HIV Therapy. Gilead satellite symposium. Geneva, Switzerland, July 1, 1998.

Winslow, D. and others. A phase II randomized open label study of adefovir dipivoxil (Preveon) in combination with indinavir, zidovudine, lamivudine and stavudine in therapy naive HIV-infected patients. Abstract 22371.

Indinavir (Crixivan)

Indinavir/AZT/3TC Shows Continued Benefits for Nearly Two Years

  • Viral load was undetectable in 78% using standard test (limit 500 copies/mL) and 66% using ultrasensitive test (limit 50 copies/mL).

An update of the original Merck 035 study of indinavir/AZT/3TC was published in the special July 1, 1998 HIV/AIDS edition of the Journal of American Medical Association. This is the longest study of combination protease inhibitor therapy to have shown a sustained reduction of HIV RNA viral load. Doses used were indinavir 800 mg three times daily, AZT 200 mg three times daily, and 3TC 150 mg twice daily. The interim 52-week data were originally published in the New England Journal of Medicine in September, 1997.

The original 97 patients had no prior therapy with protease inhibitors or 3TC. Initially, patients were randomized to the 3-drug arm, an indinavir monotherapy arm, or an AZT/3TC arm. After 24 weeks, all patients rolled over into open-label indinavir/AZT/3TC and were followed for a total of 100 weeks. Median baseline viral load was 43,190 copies/mL and median baseline CD4 count was 144 cells/mm3.

Viral load was undetectable in 78% using the standard test (limit 500 copies/mL) and in 66% using an ultrasensitive test (limit 50 copies/mL); this was an "intent-to-treat" analysis. Fifteen percent (5 of 33) of the original 3-drug arm, 39% (13 of 31) of the original AZT/3TC arm, and 29% (9 of 31) of the original monotherapy arm discontinued early due to increasing viral loads or adverse events. Only two deaths occurred during the 100-week follow-up, both in the original AZT/3TC arm (one due to Pneumocystis carinii pneumonia, one due to a heart attack not related to indinavir). Of the 33 patients originally enrolled in the 3-drug arm, 28 (85%) remained on the study for two years.

Genotypic resistance tests results were reported for the triple therapy arm. For the seven who had viral loads greater than 500 copies/mL at 100 weeks, resistance mutations for indinavir (5 of 7), 3TC (7 of 7), and AZT (5 of 7) were detected. Four entered the study with AZT resistance mutations. Two had periods of non-adherence.

The results clearly demonstrate how important it is to start triple therapy simultaneously, and the disadvantage of sequentially adding drugs. The results support the guidelines of the IAS-USA and the U.S. Public Health Service regarding combination antiretroviral therapy. Unfortunately, larger studies with people in the community do not often have results as stellar as those in this controlled trial. Fortunately, virologic failure (increased viral load) does not always translate into clinical failure in the short term.

Gulick, R.M. and others. Simultaneous versus sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100 week follow-up. Journal of the American Medical Association 280:35-41. July 1, 1998.

Holder, D.J. and others. Two-year durability of HIV-1 load suppression in patients treated with indinavir who experience virus load declines to <500 vRNA copies/mL. Abstract 12279.

How Effective is Indinavir Triple Therapy in Very Early HIV Infection?

  • Viral was undetectable for 85% (limit 50 copies/mL).
  • CD4 count increase was approximately 115 cells/mm3.

Interim data were reported from Merck 060/ICC 004, an interesting 4-year study attempting to determine the efficacy of standard indinavir triple therapy for early infection with HIV. This was an open-label study with 198 asymptomatic participants (27% women, 39% racial/ethnic minorities). Mean baseline CD4 cell count was 602 cells/mm3 and mean baseline viral load was 8,076 (3.9 log) copies/mL.

At 36 weeks, 85% achieved an undetectable viral load (limit 50 copies/mL). The mean CD4 cell increase was approximately 115 cells/mm3.. Seven participants (4%) have been classified as non-responders ("virologic failures") due to a lack of viral load response; all seven were reportedly non-adherent. Five of the seven had a 3TC resistance mutation (M184V) and one also had an indinavir resistance mutation (V82A).

Fourteen percent of enrollees discontinued the study; 46% did so due to adverse events, including fatigue, headache, kidney stones, nausea, numbness, rash, shortness of breath, Stevens-Johnson syndrome (a life-threatening allergic reaction), and vomiting.

These interim results indicate how much easier it is to achieve an undetectable viral load in HIV positive people with early infection than in those with later stage disease. This is likely due to the shorter length of time available for HIV to produce mutant variants that could become dominant when anti-HIV drugs are used. This study will continue for another three and a half years.

Leavitt, R. and others. Indinavir in combination with zidovudine (AZT) and lamivudine (3TC) in treatment-naive patients with greater than or equal to 500 cells/mm3. Abstract 12311.

Can Indinavir be Taken Every 12 Hours Instead of Every 8 Hours

  • Experimental dose is 1,200 mg every 12 hours.
  • When combined with efavirenz once daily, benefits are seen after 24 weeks.
  • Trough level of indinavir is low in twice daily regimens.

For many patients, adhering to the three-times-daily dose of indinavir with alow-fat snack can be a problem. Several trials were reported that looked at indinavir dosing twice daily. [Editor's note: On September 18, Merck and Company announced that it was discontinuing clinical trials involving twice-daily use of its protease inhibitor indinavir, (except for trials of dual protease inhibitors).]

Twice daily indinavir plus efavirenz (Merck study 067). In a randomized, open-label, 48-week study, there were no significant differences between 1) indinavir 1200 mg plus efavirenz 300 mg, each twice daily, and 2) indinavir 1,000 mg every eight hours plus efavirenz 600 mg once at bedtime. The 71 patients (11% women, 37% racial/ethnic minorities) had no prior protease inhibitors or NNRTI therapy. Mean baseline viral load was 36,748 copies/mL and mean baseline CD4 count was 334 cells/mm3.

After 24 weeks, approximately 50% of each arm had an undetectable viral load (limit 50 copies/mL), using an "intent-to-treat" analysis. CD4 cell counts increased by approximately 125 cells/mm3 in each arm.

In measuring mean indinavir blood levels ("area under the curve"), there was little difference between the two arms. However, the lowest, or "trough," level of indinavir was much lower in the twice daily arm. Researchers have determined from other studies that viral load response is correlated with the trough level of indinavir. Mean peak levels were somewhat higher in the twice daily arm.

Discontinuation rates were 24% and 18%, respectively for the two arms. However, one-third in each arm discontinued due to adverse events, including rash, dizziness, nausea, vomiting, and fatigue. There were no kidney stones or urinary complications seen. Half of each arm had dizziness, cognitive problems, or sleep problems, while 40% of each arm had diarrhea. HIV viral load rebound occurred in 24% and 17% of the two arms, respectively, half of which was due to poor adherence. Almost all (93%) of those who had viral load rebound had an efavirenz resistance mutation (K103N).

Twice daily each of indinavir plus nelfinavir (Merck study 061). In a 72-week, drug interaction and follow-up study, twice daily doses of indinavir (1,000 mg) plus nelfinavir (750-1,000 mg) led to lower trough levels of each drug than with standard 3-times-daily dosing. All participants had no prior protease inhibitor therapy. Of the 21 patients (all men) enrolled, eight discontinued (two-thirds due to increasing viral load), and 53% of the remaining 13 had nucleoside analog drugs added after at least 18 weeks. Of the 13 patients still enrolled at 48 weeks, 38% had an undetectable viral load (limit 50 copies/mL). The median CD4 count increase was 198 cells/mm3. Moderate or worse (grade 2 or higher) adverse events included diarrhea (29%), nausea (19%), bloating/cramps (19%), kidney stones (10%), and rash (5%). Among those with adverse events, only one patient with rash discontinued. Among those with increasing viral loads, two-thirds had developed a protease inhibitor resistance mutation.

Twice daily of indinavir plus AZT/3TC (Merck study 054). This trial included twice daily dosing of indinavir at 1,000 or 1,200 mg. Earlier results were reported at the 5th Retroviral Conference earlier this year. The regimens combined either twice daily indinavir or 3-times-daily indinavir with AZT/3TC. All 87 patients were naive to protease inhibitors and 3TC, and were randomized to one of three arms. Interim results at 32 weeks were reported for 38 of 87 (44%) patients. The median baseline HIV RNA viral load was 4.7 log copies/mL and the median baseline CD4 count was 266-294 cells/mm3. After 32 weeks, 60% of both the twice-daily arms achieved an undetectable viral load (limit 50 copies/mL) compared with 40% of the 3-times-daily arm. Median CD4 counts increased by 50 cells/mm3 in both the twice-daily arms, compared with 160 cells/mm3 in the 3-times-daily arm.

Serious adverse events were highest in the 1,200 mg twice daily arm (13%), with a rate of only 3% in the 1,000 mg twice daily arm. The rate of kidney stones was highest in the 1,200 mg arm (13%) with a lower rate in the 1,000 mg arm (3%). Serious nausea and vomiting occurred in just over half (51-56%) of all three arms. Discontinuation rates were 40% in both the 1,200 mg arm and 3-times-daily arm, but only 25% in the 1,000 mg twice-daily arm.

Havlir, D. and others. Sixteen-week (poster showed 24 week) follow-up of indinavir sulfate administered Q8 hours versus Q12 hours in combination with efavirenz. Abstract 12290.

Nguyen, B.-Y. and others. Thirty-two week follow-up of indinavir sulfate administered Q8 hours versus Q 12 hours in combination with zidovudine and lamivudine. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, Illinois, February 1-5, 1998. Abstract 374.

Saah, A. and others. Co-administration of indinavir and nelfinavir: pharmacokinetics, tolerability, anti-viral activity and preliminary viral resistance. Abstract 22352.

Skidmore J. HIV-AIDS News (press release) from Merck Sharpe and Dohme. June 28, 1998.

Young, S. and others. Indinavir 12 hour dosing an alternative to 8 hour dosing regimen: a pilot study (total of 25 patients). Abstract 60484.

Kidney Pain and High Indinavir Levels

  • Patients with kidney pain due to indinavir have higher than normal blood levels of the drug.
  • Reducing the dosage decreased the drug levels in six patients; viral load remained undetectable after two months.
  • Patients with kidney stones may absorb more indinavir.
  • Indinavir blood level tests are suggested.

Kidney stones and indinavir crystals in the urine are extremely painful complications of this potent protease inhibitor. Symptoms may include back and/or groin pain, painful urination, and blood in the urine. Researchers from Erasmus Medical Center in Rotterdam, the Netherlands, determined through a small study that kidney stones may be due to excessively high drug levels. The authors presented a case series comparing indinavir blood levels of 17 patients (29% women) with kidney stones with levels in 14 control patients without urologic symptoms. All were taking the standard indinavir dose of 800 mg every eight hours in a combination regimen. Blood was drawn for testing 1.5-8 hours after the last indinavir dosage.

Results indicated that 93% of the symptomatic arm had drug levels significantly higher than those of the control group; 80% of the symptomatic arm had levels higher than one standard deviation above the mean of the control group. The median drug concentration of the symptomatic group was 2.25 times higher than that of the control arm. One patient’s level was over 11 times that of the control arm’s mean level! However, not every patient in the symptomatic arm had a high indinavir level.

In six patients from the symptomatic arm with high indinavir levels, dosage was decreased to 600 mg every eight hours. This adjustment caused drug levels to fall into the normal range. After two months of follow-up, five of the six did not develop additional urologic symptoms and all maintained an undetectable HIV viral load (limit 400 copies/mL).

The authors concluded that "urologic complications during indinavir treatment are associated with elevated indinavir plasma levels and may therefore be a sign of indinavir intoxication." They also conclude that "indinavir plasma levels should be monitored upon presentation of urologic complaints." The difficulty with the recommendation is that indinavir drug level tests are currently a research tool and standardization is lacking. The reasons why some patients have much higher blood levels of indinavir are not known. It could be that these people absorb more of the drug, metabolize the drug more slowly, or have more free drug in their blood plasma. It is quite possible that there are other mechanisms of kidney stone formation not associated with high drug levels. Patients taking indinavir who have had kidney stones should not decrease their dosage without consulting their physician.

Dieleman, J. and others. Urologic complaints in relation to indinavir plasma levels in HIV-infected patients. Abstract 12372.

Patients with Kidney Stones have a Higher Urine pH

  • Making urine more acidic does not decrease the rate of indinavir-related kidney stones.

Indinavir is known to be more soluble in acidic (lower pH) urine. Researchers from Merck have contended that it would be extremely difficult to lower the urine pH enough to decrease the rate of urinary stone formation. Two separate reports addressed urine acidity and kidney stone formation.

In a retrospective study from the University of Colorado, researchers examined the charts of 13 HIV positive patients who developed a probable indinavir-induced kidney stone, and 14 control patients who took indinavir for at least six months but did not develop complications. All kidney stone patients had back pain and bloody urine; kidney stones were confirmed by X-rays or computed tomography (CT) scanning.

The kidney stone group had a significantly higher (less acidic) urine pH than the control group. The mean urine pH in the kidney stone group was 6.4, compared to 5.6 in the control group (a 1-point difference on the test represents a 10-fold difference in acidity). Also, 62% of kidney stone patients had a urine pH of six or higher, compared to only 21% of control patients, a statistically significant difference.

The authors concluded that indinavir patients with a higher urinary pH may be more likely to develop kidney stones. They suggest that developing dietary guidelines that result in a lower urinary pH may help to avoid this complication.

In the second study, researchers from Suresness, France, tried to show that decreasing the urine pH could decrease the rate of kidney stone formation. Unfortunately, they were unsuccessful. The researchers wanted to determine whether their patients’ urinary pH could be lowered by diet modification. They asked patients taking indinavir to test the pH of their urine for ten days while consuming their normal diet, for a 10-day period during which they avoided alkaline (high pH) water and took a daily supplement of 500 mg vitamin C (ascorbic acid), and finally during a 10-day period during which they avoided alkaline water and drank 11 ounces daily of Coca Cola (carbonated beverages are somewhat acidic). Drinking Coca Cola did decrease urine pH, but did not prevent recurring kidney stones in two patients. Vitamin C did not change urine acidity. It is still possible, however, that other dietary modifications could result in a lowered urine pH that could decrease the rate of kidney stones.

Gerber, J. and other. Evaluation of urinary pH and specific gravity in the development of indinavir induced renal stones. Abstract 12394.

Zucman, D. and others. Urinary acidification and the risk of nephrolithiasis due to indinavir. Abstract 12328.

Kidney Stones Associated with Higher Temperatures, But Not Humidity

While the rain in Spain may stay mainly on the plane, indinavir-induced kidney stones in Spain have been significantly associated with higher outdoor temperatures. Researchers from the Hospital Clinic in Barcelona measured the rate of indinavir-related kidney stones during different months. They compared those monthly rates with weather information. Results showed that kidney stones occurred at a higher rate in the late summer and early autumn. There was a significant association between kidney stone rates and higher outside temperature, but not with humidity or outside pressures. The authors hypothesize that higher outside temperatures would be associated with increased sweating, lower total body water, and an increased risk of kidney stones. They suggest that during these times or in locations with "Mediterranean weather," an additional increase of daily fluid consumption may be necessary for patients taking indinavir. Merck already recommends taking 48 ounces (1.5 liters) of fluid daily.

Martinez, E. and others. Indinavir-related nephrolithiasis is associated with environmental temperature. Abstract 12399.

Should Indinavir Blood Levels be Measured?

There is an ongoing controversy about whether measuring blood levels of anti-HIV drugs would be beneficial. In many areas of medicine, routine drug level testing is standard. However, according to the IAS-USA updated HIV treatment guidelines, "Therapeutic [anti-HIV] drug level monitoring is becoming available to clinicians, but its utility as a monitoring tool is a subject of considerable debate and cannot be recommended at this time." Currently, no anti-HIV drug level test is FDA-approved. However, several specialty labs do have such tests available. Several presentations in Geneva addressed the issue of drug level testing. While different authors had varying answers, it appears that there are some situations in which there may be benefits.

A major issue is whether drug levels of indinavir correlate with anti-HIV benefits. Researchers from Merck presented a poster that combined data from five studies and found no significant relationship between trough (lowest) blood levels of indinavir and anti-HIV efficacy, as measured by decreases in viral load. However, the authors acknowledge that there may not be detectable differences when the indinavir level is in the optimal (therapeutic) range or at the "high end of the dose-response curve." Another limitation is that all five studies used indinavir monotherapy, something that is not done today.

Researchers from Pharmacie Hospital in Bicetre, France, also found no significant relationship between indinavir blood levels and HIV viral load decreases in 95 HIV-positive patients taking indinavir in standard triple combinations. However, they acknowledge that drug level tests may have a role when there is no viral load response or when viral load is increasing. They also state that there may be benefits when the patient has liver disease (which could >affect drug metabolism) or to ensure an adequate drug level when indinavir is taken with other drugs that could change the indinavir concentration. They concluded that indinavir drug levels should always be significantly greater than 70 ng/mL. This is the concentration that inhibits 95% of HIV growth in vitro (the IC95%).

In another study, researchers from Terassa, Spain, found no significant relationship between therapeutic indinavir blood levels and HIV viral load response. In 31 HIV positive patients taking indinavir combination therapy, 95% of patients with a detectable viral load had drug levels much higher than the IC95% 2-8 hours after a dose. Moreover, after eight months, only one-third had an undetectable viral load (limit 80 copies/mL), even though 87% had therapeutic drug levels when tested. This could be due to indinavir resistance, or due to patients taking a dose of indinavir a few hours before a blood test was done.

In contrast to the above studies was a poster presented by researchers from the University Hospital in Nijmegen, the Netherlands. In a study of 65 HIV positive patients taking indinavir triple therapy, the authors found a highly significant relationship between low indinavir blood levels and failure of viral load reduction. Moreover, there was a dose-response relationship that further substantiated their findings: the lower the drug level, the more likely a patient was to fail therapy. The authors concluded that "monitoring plasma concentrations of protease inhibitors may contribute to improved virological response."

There are other factors to consider in the debate about drug level testing. First, these drugs have their effects mostly in immune tissue (e.g., lymph node) cells. A measurement from the blood plasma does not measure drugs levels "where the action is." Increasing drug levels in the plasma does not necessarily mean that drug levels will similarly increase in immune cells. Second, if a patient is not adhering to their drug regimen, then expensive drug level tests are a waste of time and money, not to mention an unnecessary needlestick for the patient. A patient knowing that a drug level test is scheduled may simply take one properly timed dose to "look good" and avoid a lecture on adherence. Third, there is significant variability from patient to patient in terms of drug levels in the blood, particularly for the protease inhibitors. Fourth, the compound measured by the tests may not be the active form of the drug; metabolism of several anti-HIV drugs (in particular the nucleoside analogs) is necessary to achieve an active form. Fifth, measuring the concentration of one drug may not show the whole picture, since therapy today uses several drugs simultaneously. Finally, many drugs are tightly bound to blood proteins, thus the plasma level of free (non-bound) drug may not tell the whole story.

One presentation addressed the feasibility of testing indinavir drug levels in saliva; the salivary indinavir concentration was 52% of that in blood plasma, and the two measurements showed a high degree of correlation. The authors concluded that random saliva testing might be used to assess adherence.

While the debate about drug level testing will continue, it is likely that there will be some benefits for adherent patients who have persistently detectable or increasing HIV viral loads, and possibly for those who develop kidney stones and/or urinary complications due to indinavir.

Carpenter, C.C.J. and others. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA panel. Journal of the American Medical Association 280(1):78-86. July 1, 1998.

Chodakewitz, J. and others. Relationships between indinavir pharmacokinetics and antiviral activity in phase I/II trials. Abstract 42266.

Dalmau, D. and others. Indinavir pharmacokinetics and their correlation with virologic and immunologic parameters. Abstract 42276.

Hugen, P.W.H. and others. Saliva as a possible specimen for monitoring compliance and plasma levels in patients treated with indinavir. Abstract and oral/poster presentation 512/32330.

Moyer, T. and others. Methods to measure protease inhibitor and reverse transcriptase inhibitor concentrations in human plasma. Abstract 42277.

Perello, L. and others. Therapeutic drug monitoring in patients receiving indinavir. Abstract 42272.

Nelfinavir (Viracept)

Twice Daily Nelfinavir

  • 1,250 mg twice daily nelfinavir is essentially equivalent to the standard 750 mg dose three timesdaily.
  • 1,250 mg dose twice daily was combined with soft-gel saquinavir (1,000-1,200 mg twice daily).
  • 500-750 mg dose twice daily was combined with ritonavir (400 mg twice daily)

Several studies reported in Geneva used the experimental twice-daily nelfinavir dose of 1,250 mg. Most were combined with the experimental twice-daily soft-gel saquinavir (Fortovase) dose of 1,200 mg plus nucleoside analogs. It appears that the twice-daily 1,250 dose of nelfinavir is essentially equivalent to the standard thrice-daily 750 mg dose (except when combined with ritonavir). However, the trough level immediately before the next dose is somewhat lower with twice-daily dosing. Better results were seen in people who never before used anti-HIV therapy. However, even salvage therapy was quite successful in a small study from San Francisco General Hospital utilizing the 4-drug combination of nelfinavir (1,250 mg twice daily)/saquinavir (1,200 twice daily/abacavir (300 mg twice daily)/efavirenz (200 mg twice daily).

The 48-week interim data from a Phase III study (study 542) of twice-daily nelfinavir was presented. The randomized, double-blind study enrolled 288 HIV-positive patients from Europe (14% women). The study compared 1,250 mg twice-daily nelfinavir with the standard 750 mg 3-times-daily dosage, both in combination with d4T and 3TC. Originally, the twice-daily arm included three different doses (750 mg, 1,000 mg, and 1,250 mg). However, when the results of study 511 revealed that the 500 mg 3-times-daily dose led to significantly lower levels of undetectable viral load than the 750 mg 3-times-daily arm, the current study was modified so that all people taking twice-daily nelfinavir received a dosage of 1,250 mg. Mean baseline viral load was 5 log copies/mL and mean baseline CD4 count was approximately 265 cells/mm3. All had less than six months of prior anti-HIV therapy and less than two weeks prior protease inhibitor therapy.

Interim 48-week results were presented for 143 patients. Undetectable viral load levels (limit 50 copies/mL) were 65-70% for both arms. The twice-daily arm showed a slightly faster response time. The mean CD4 cell increase was 189 cells/mm3 for the twice-daily arm and 166 cells/mm3 for the 3-times-daily arm.

No serious adverse events were reported. However, events of moderate-to-severe intensity did occur with approximately equal rates in both arms. Moderate-to-severe diarrhea occurred in 12-13% of both arms, and moderate-to-severe nausea occurred in 2% of the twice-daily arm and 4% of the 3-times-daily arm. One patient in the twice-daily arm developed diabetes thought to be due to nelfinavir. Approximately 12% of patients from each arm discontinued the study; however, only four patients (2%) discontinued due to nelfinavir-related adverse events (two due to diarrhea and two due to rash). No patients withdrew from the 3-times-daily arm due to nelfinavir-related adverse events. One person in the twice-daily arm and two patients in the 3-times-daily arm withdrew due to nelfinavir failure. Two patients in each arm discontinued due to non-adherence.

Nelfinavir blood plasma levels were measured. While the median drug concentration ("area under the curve") was somewhat higher in the twice-daily arm than in the 3-times daily arm, the trough level was slightly lower for the former arm than the latter arm.

In the Women First study, all 51 participants were women. One arm received twice-daily nelfinavir (1,250 mg) and saquinavir (1,000 mg) plus d4T/3TC. A second arm received 3-times-daily nelfinavir (750 mg) and hard-gel saquinavir (600 mg) plus standard doses of d4T/3TC. The open-label study included only participants without prior protease inhibitors therapy.

Interim 24-week results were presented for 31 patients (61%). Viral load was undetectable for 63% in both arms (limit 50 copies). CD4 counts increased by 146 cells/mm3 for the twice-daily arm and by 138 cells/mm3 for the 3-times-daily arm. Moderate-to-severe adverse events included diarrhea (10% in the twice-daily arm vs 0% in the 3-times-daily arm), vomiting (5% of each arm), and rash (0% in the twice daily arm vs 8% in the 3-times-daily arm).

Nelfinavir blood levels ("area under the curve") were 53 milligram-hours per liter in the twice-daily arm and 72 milligram-hours per liter in the 3-times-daily arm, and the trough level decreased approximately 15-20% in the twice-daily arm. Area under the curve concentrations for saquinavir were somewhat higher in the 3-times-daily arm. Trough saquinavir concentrations were almost equivalent. Viral load decreased in both blood plasma and cervical secretions. The study will continue for 12 months.

It appears that the twice daily 1,250 mg dose of nelfinavir is essentially equivalent to the standard 750 mg 3-times-daily dose. When combined in a double protease inhibitor combination, the results are also quite promising. Hopefully, this combination will not lead to the high rates of protease inhibitor side effects that occur when ritonavir is combined with saquinavir.

Cohen, C. and others. Potent and convenient Fortovase (saquinavir) soft gel capsule BID regimens in combination with 2 nucleosides or nelfinavir plus 1 nucleoside in HIV-1 infected patients. Abstract 12314.

Deeks, S. Twenty-week HIV RNA response and correlation with baseline phenotypic drug susceptibility during treatment with a novel quadruple salvage regimen after failure of indinavir combination therapy. Abstract 22490.

Farnsworth, A. and others. Women First: A study of the effects of treatment in women + HIV-infected with combination nelfinavir saquinavir, stavudine and lamivudine. Abstract 12305.

Flexner, C. and others. Steady-state pharmacokinetic interactions between ritonavir, nelfinavir and the nelfinavir active metabolite M8 (AG1402). Abstract 42265.

Gallant, J. and others. Phase II study of ritonavir-nelfinavir combination therapy: an update. Abstract 12207.

Lohmeyer, J, and others. Combined nelfinavir/saquinavir protease inhibitor treatment in a BID regimen as salvage therapy in advanced HIV disease. Abstract 12303.

Moyle, G. and others. Study of protease inhibitor combination in Europe (SPICE): saquinavir soft gelatin capsule plus nelfinavir in HIV-infected individuals. Abstract 290/12222.

Peterson, A. and others. Long-term comparison of BID and TID dosing of nelfinavir in combination with stavudine (d4T) and lamivudine (3TC) in HIV patients. Abstract 12224.

Saah, A. and others. Co-administration of indinavir and nelfinavir: pharmacokinetics, tolerability, anti-viral activity and preliminary viral resistance. Abstract 22352.

Sension, M. and others. Safety and efficacy of BID dosing of Viracept (nelfinavir mesylate) with two NRTIs. Abstract 60631.

Treating Nelfinavir-Related Diarrhea

  • Pancrelipase (Ultrase MT20) effective for 96% when over-the-counter loperamide (Imodium AD) is not helpful.
  • Daily psyllium fiber decreases diarrhea in 55%.
  • Loperamide response occurs in 32%.
  • Diphenoxylate plus atropine (Lomotil) was least effective.
  • The development of diarrhea after starting nelfinavir is correlated with a higher baseline viral load and a lower baseline CD4 count.

Mild-to-severe diarrhea is the most common side effect from nelfinavir. Two posters attempted to determine which therapies are the most helpful.

The first report was from a chart review conducted by the Camino Medical Group in Sunnyvale, California. Forty-seven patients had nelfinavir-related diarrhea; none had diarrhea prior to starting nelfinavir. Five were excluded from the analysis; of the remaining 42, 14% were women. Baseline viral load was less than 30,000 copies/mL in 24% and at least 30,000 copies/mL in 76%.

Response to over-the-counter loperamide occurred in 32%. Pancrelipase was prescribed for 26 (60% of total) non-responders to either loperamide or diphenoxylate/atropine. The dose was 1-2 capsules with meals/snacks. Interestingly, 96% responded to pancrelipase. One patient who did not initially respond to one capsule did so after the dose was increased to two capsules. After four weeks of pancrelipase, 85% had a significant viral load decrease from baseline. Blood drug levels were within the expected range.

The authors concluded that for those nelfinavir patients whose diarrhea does not respond to standard over-the-counter loperamide or prescription diphenoxylate/atropine, pancrelipase is quite effective. This supplement does not appear to interfere with either nelfinavir absorption or distribution or with virological response.

Pancrelipase capsules contain a pig-derived pancreas gland enzyme concentrate including amylase, lipase, and protease. The supplement is FDA-approved for pancreas-deficiency states including chronic pancreatitis and cystic fibrosis. While the mechanism of action of pancrelipase in improving nelfinavir-related diarrhea is unknown, it is possible that the supplemental digestive enzymes metabolize food that otherwise might not have been completely metabolized. Alternatively, the supplemental enzymes may decrease bowel transit time and/or increase water absorption from the intestine.

It is quite possible that pancrelipase may have similar anti-diarrheal benefits for those taking other protease inhibitors. While many physicians are already prescribing pancrelipase, this is the first report to document its benefits.

The second report was a telephone survey of 77 HIV/AIDS patients (12% women; 39% racial/ethnic minorities) in a clinical practice in Santa Fe, New Mexico. All had been prescribed nelfinavir for more than three months. Eighty-seven percent reported diarrhea while taking the drug. Twenty-six percent reported using daily psyllium (Metamucil, Konsyl, other brands) to help improve diarrhea; psyllium is a husk fiber available without a prescription. Among psyllium users, 55% stated that the supplement helped them adhere to nelfinavir treatment. Those who indicated that the supplement did not improve adherence had a lower CD4 count (207 cells/mm3) than those who said it did help (325 cells/mm3).

Fifty-six percent reported using some other therapy to help relieve diarrhea. Among psyllium users, 55% reported less frequent stools and 40% reported firmer stools. Fifty percent reported using another anti-diarrheal product (71% were using loperamide and 5% each were using herbal tea/medicine, Pepto Bismol, glutamine, Kaopectate, Fibercon, and diet change).

In a poster from the University Health Center in Detroit, MI, researchers reported that the development of diarrhea after starting nelfinavir was statistically associated with a higher baseline viral load and a lower CD4 count; furthermore, baseline CD4 counts were lower and viral loads were higher as the severity of diarrhea increased. The authors also found that increases in CD4 counts after starting nelfinavir were significantly smaller for patients reporting diarrhea. However, changes in plasma viral load after starting the drug did not differ in those with or without diarrhea.

Hawkins, T. Nelfinavir-associated diarrhea is manageable with nonprescription medications. Abstract 12401.

Kosmyna, J. and others. The incidence and severity of diarrhea in HIV+ patients from a large, urban medical center who have taken nelfinavir in the past twelve months. Abstract 12392.

Razzeca, K. and others. The treatment of nelfinavir-induced diarrhea. Abstract 12383.

Does HIV Viral Load Response Correlate with Nelfinavir Blood Levels?

  • Results suggest potential benefits of measuring drug levels.

Two separate presentations indicated that viral load reductions are significantly associated with therapeutic nelfinavir levels in blood plasma. In the first study, researchers from Slotervaart Hospital in the Netherlands tested 30 HIV-infected patients from the Amsterdam Duration of Antiretroviral Medication (ADAM) study. The 4-drug combination of nelfinavir/saquinavir/d4T/3TC was used. Five viral load measurements for each patient were used to create graphs showing viral load decline in the first eight weeks after starting treatment. When blood was drawn for viral load measurements, nelfinavir and saquinavir drug levels were tested. A significant relationship was seen between peak nelfinavir blood levels and viral load decline. However, there was no significant relationship between saquinavir levels and viral load decline.

In the second study, researchers from Agouron Pharmaceuticals reported the relationship between nelfinavir drug levels and viral load response in 297 patients without prior anti-HIV therapy in a Phase III study comparing 500 mg and 750 mg doses of nelfinavir. Blood for testing was drawn two hours after an oral dose of nelfinavir. Mean nelfinavir drug levels were statistically associated with viral load undetectability (limit 50 copies/mL) at week 24. An association was also found between the nelfinavir active metabolite M8 and viral load undetectability.

These two studies add to our knowledge about the value of nelfinavir blood levels and HIV viral drug responses.

Hoetelmans, R.M.W. and others. The rate of decline of HIV-1 RNA in plasma correlates with nelfinavir concentrations in plasma. Abstract and oral/poster presentation 510/42259.

Kerr, B. and others. Virologic response-plasma drug concentration relationship in phase III study of nelfinavir mesylate (Viracept). Abstract 12304.

Reiser, M. and others. Virological efficacy and drug levels of nelfinavir plus saquinavir as salvage therapy in HIV-infected patients refractory to standard triple therapy. Abstract 22338.

Hives Do Not Reappear After Desensitization Protocol

Hives (itchy red or pink welts in the skin) are an uncommon side effect that has been reported with both indinavir and ritonavir. The condition is characteristic of an allergic or hypersensitivity reaction. In Geneva, researchers from the Maladies Respitatoires Hospital in Seine, France, reported that they were able to maintain two patients with nelfinavir-related hives on therapy using a 1-day desensitization protocol.

The researchers reported that three patients developed generalized hives eight days after started nelfinavir combination therapy. All had low CD4 counts (6-54 cells/mm3) and high viral loads (103,125-370,000 copies/mL). The three were also taking TMP-SMX (Bactrim, Septra) once daily to prevent PCP; this drug also has hives as a side effect. The condition disappeared after nelfinavir was stopped and antihistamines were given to block the allergic reaction. Six days later, one patient restarted nelfinavir and hives recurred.

A nelfinavir desensitization protocol was started between two and 12 weeks after nelfinavir was stopped. Two of the patients received 12 doses of nelfinavir every 30 minutes, from 25 micrograms to 1,000 milligrams in one day, followed by 750 mg three times daily. The third patient received 750 mg of nelfinavir on day 1 and increased his dose by 750 mg every three days on a 3-week protocol, up to 750 mg three times daily (note that this regimen could increase the risk of nelfinavir resistance). The first two patients again experienced mild and transient hives on day 2 and day 10, respectively. The symptoms were well controlled with an antihistamine. One patient decided to discontinue nelfinavir, and the other two were successfully desensitized.

This experimental desensitization protocol may represent an option for those HIV positive patients who need it. Similar type of protocols exist for desensitization to TMP-SMX.

Demoly, P. and others. Nelfinavir-induced urticaria and successful desensitization. Abstract 60967.

Fuchs, A. and others. Indinavir-induced urticaria and leukocytoclastic vasculitis; cross-reactivity with ritonavir. Abstract 60274.

Ritonavir (Norvir)

Ritonavir plus ABT-378

  • Preliminary Phase II study (M97-720) of ABT-378 plus ritonavir included 32 participants (6% women, 28% racial/ethnic minorities).
  • 200-400 mg ABT-378 taken with 100 mg ritonavir (both twice daily) plus AZT/3TC; no food restrictions.
  • After 24 weeks, viral load was undetectable (limit 400 copies/mL) for 91% and there was a median CD4 count increase of 150 cells/mm3 ; results were for 11 participants (34%) reaching 24 weeks.
  • Moderate adverse effects included diarrhea (31%), weakness and headache (9%), and stomach pain (6%); therapy was well-tolerated and none discontinued the study.
  • There were no significant differences between the two doses of ABT-378.

Japour, A. and others. Safety and efficacy of ABT-378/ritonavir in antiretroviral naive patients: preliminary phase II results. Late-breaker abstract 4/12460

Ritonavir Causes Faster Breakdown of Thyroid Medication.

A man whose thyroid measurements were stable while taking prescribed thyroid hormone replacement therapy showed evidence of faster breakdown of thyroid hormone after ritonavir was started. Even doubling his thyroid dose did not lead to normal thyroid measurements, and indinavir was substituted for ritonavir. Subsequently, his thyroid medication was reduced to the original dose and his thyroid measurements returned to near normal. Other people with HIV who are taking thyroid hormone supplements may have a similar problem. Ritonavir is the most likely culprit because of all the protease inhibitors it most strongly affects the CP450 liver enzyme system.

Tseng, A. and others. Interaction between ritonavir and levothyroxine. Abstract 60571.

Always watch for outdated information. This article first appeard in 1998. This material is designed to support, not replace, the relationship that exists between you and your doctor.

Copyright © 1998 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.