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Selected Highlights from the 7th CROI: Combination Drug Studies

Spring, 2000

Treatment-Naive Persons

Emtricitabine (Coviracil, FTC) Plus ddI and Efavirenz (Sustiva)

Using a strict intent-to-treat analysis, this three-drug combination led to an undetectable HIV RNA viral load in 98% of subjects (limit of detection 400 copies/mL) at 24 weeks. The undetectability rate was 93%, using a lower limit of 50 copies/mL. Viral load undetectability rates were essentially equivalent for those with a baseline viral load greater than or less than 100,000 copies/mL. CD4 cell counts increased by a mean of 151 cells/mm3. Forty treatment-naive HIV positive persons (22% women) were enrolled. The dose of FTC was 200mg once daily. The once-daily regimen consisted of only seven pills (four pills plus three capsules) on an empty stomach at bedtime. FTC and ddI are NRTIs, while efavirenz is an NNRTI.

The median baseline viral load was 4.8 log copies/mL, while the median baseline CD4 cell count was 373 cells/mm3. Adverse events that were severe or life threatening occurred in 15% of participants. These included increased muscle enzyme (CPK, creatine phosphokinase), liver enzymes ALT (alanine aminotransferase) and AST, and increased triglycerides. Moderately abnormal laboratory events occurred in another 28%. These were increased triglycerides (8%), increased CPK (5%), low white cell count, or leukopenia (5%), increased cholesterol (3%), increased amylase, a pancreas enzyme (3%), and increased bilirubin (3%). Efavirenz side effects were mostly transient including dizziness (45%), sleep problems (30%), mood changes including depression (28%), and headaches (28%). Weakness occurred in 20%. Other mild-to-moderate side effects included rash (10%), abdominal cramping (15%), and diarrhea (33%). Only one person (2.5%) discontinued the study in the first 24 weeks.

This once-daily HAART regimen with only seven pills represents the highest percentage of viral load undetectability in treatment-naive persons at 24 weeks ever reported. The lead author was J.M. Molina, M.D., from Paris. Dr. Molina mentioned that all of the subjects in the study were highly motivated.


ABT-378 (Lopinavir) Plus Ritonavir, d4T, and 3TC

After 72 weeks, this four-drug combination led to an HIV viral load undetectability rate of 82% (limit of detection 400 copies/mL) in an intent-to-treat analysis. With a limit of 50 copies/mL, 80% of study subjects had an undetectable viral load. These viral load results are among the best ever reported for treatment-naive persons. Viral load responses were nearly equivalent for those with baseline viral loads both greater than and less than 100,000 copies/mL. There were 100 treatment-naive subjects (4% women, 35% non-White) who took the experimental PI ABT-378 at a dose of 200-400mg with a ritonavir dose of 100-200mg, both twice daily. After the first 48 weeks, the ritonavir dose was 100mg, while the ABT-378 dose was 400mg. The ABT-378/ritonavir double PI drug regimen was combined in the same capsule.

The median baseline HIV RNA viral load was 4.9 log copies/mL, while the median CD4 cell count was 361 cells/mm3. The median CD4 cell count increase was approximately 275 cells/mm3. Adverse events that were moderate or worse included diarrhea (more than three stools daily) (21%), nausea (15%), abnormal stools (three or fewer stools daily) (8%), weakness (7%), headaches (7%), and vomiting (5%). Severe or life-threatening laboratory adverse effects were increased cholesterol (14%), increased triglycerides (12%), and increased liver enzymes (8%). Half of those with increased liver enzymes had chronic hepatitis B or C. Impressively, only 1% discontinued the study due to adverse events related to study drugs. The lead author was Roy Gulick, M.D., from Cornell University in New York.

Amprenavir, Abacavir, and AZT/3TC

After 28 weeks of treating primary (acute) HIV infection with a five-drug, two-drug class regimen, there was an HIV RNA viral load undetectability rate of 80% (limit of detection 50 copies/mL). Using an ultrasensitive test (limit of detection 5 copies/mL), the undetectability rate at 28 weeks was 35%. CD4 cell counts increased by approximately 210 cells/mm3. One hundred fifty-one persons were recruited, but only 98 had completed 28 weeks. After one year of this five-drug HAART regimen, subjects will be randomized to HAART alone, HAART plus the ALVAC experimental HIV vaccine, or HAART plus the ALVAC and Remune (inactivated HIV) vaccines. The entire study is planned to last at least 24 months. The lead author was David Cooper, M.D., D.Sc., from St. Vincent's Hospital in Sydney, Australia.

Nevirapine (Viramune) Plus AZT and 3TC

In treatment-naive persons, nevirapine triple combination therapy is as effective for persons with a high baseline viral load (greater than 100,000 copies/mL) as it is for those with a low baseline viral load. The 48-week analysis was a substudy of an international nevirapine combination trial (BI 1090) with 2,256 treatment-naive subjects. Among the first 171 subjects (35% women, 57% non-White) who took nevirapine/AZT/3TC, 55% had a baseline viral load greater than 100,000 copies/mL, while 25% had a viral load greater than 500,000 copies/mL.

The mean baseline viral load was 5.15 log copies/mL, while the mean CD4 cell count was 97 cells/mm3. The 12-month results showed that 45% of those in the triple therapy arm had an undetectable viral load (limit of detection 50 copies/mL) in a strict intent-to-treat analysis. Those subjects with a baseline viral load less than the median had a 47% viral load undetectability rate, while those above the median had a 46% undetectability rate. The mean CD4 cell count increase was 137 cells/mm3. The triple combination of nevirapine/AZT/3TC amounts to only four pills daily when the Combivir formulation of AZT/3TC is used. Similar findings of an equal viral load response among those with high and low baseline HIV viral loads also have been reported with efavirenz triple-combination therapy. The lead author was Richard Pollard, M.D., of the University of Texas at Galveston.

Treatment-Experienced Persons

ABT-378 Plus Ritonavir, Nevirapine, and Two NRTIs

Among 70 persons who previously had a detectable HIV RNA viral load while taking their first regimen, 70% displayed an undetectable viral load (limit of detection 400 copies/mL) in a strict intent-to-treat analysis after 48 weeks of this five-drug regimen. With a test using a lower limit of 50 copies/mL, the undetectability rate was 60%. The CD4 cell count increased by 125 cells/mm3. The study included 10% women and 34% non-Whites. The experimental PI ABT-378 400mg and ritonavir 100-200mg were taken in a combination capsule twice daily.

All subjects had prior experience with only one PI plus two NRTIs. Among those 57 subjects who had had baseline genotype resistance tests, 63% had a 4-fold or higher decreased susceptibility (resistance) to their previous PI. (A genotype resistance test evaluates a person's HIV strain for mutations that have been previously associated with resistance to that drug.) No prior experience with a non-NRTI drug was allowed. The two NRTIs in the new regimen were changed from those in the previous three-drug regimen and had to include at least one new one. The median baseline viral load was 4 log copies/mL.

Moderate or worse adverse events included diarrhea (21%) and weakness (6%). Severe or life-threatening abnormal laboratory tests included increased cholesterol (26%), increased triglycerides (25%), and increased liver enzymes (16%). Only three subjects (4%) stopped therapy due to adverse events related to a study drug. The total discontinuation rate was 17% (including 13% for other reasons). The lead author was Steve Deeks, M.D., of San Francisco General Hospital.

FDA approval of the combined formulation of ABT-378 plus ritonavir is very likely during the year 2000. The fixed-formulation capsule will have 133mg of ABT-378 plus 33mg of ritonavir, at a dosing of three capsules approximately every 12 hours.

Interleukin 2 (IL-2, Aldesleukin, Proleukin) Plus HAART

Researchers from France have used IL-2 in persons with later-stage HIV disease taking HAART who had undetectable viral loads, but in whom the CD4 cell count did not increase very much. The results were quite good. Due to the CD4 cell count increases in the ANRS 082 (ILSTIM) study, the French National Drug Agency has endorsed a recommendation to add IL-2 to a person's HAART regimen if there is not a sufficient CD4 cell count increase. A CD4 cell count greater than 200 cells/mm3 is needed to avoid most of the severe, life-threatening AIDS OIs. Christine Katlama, M.D., of the Hôpital Pitié-Salpêtrière in Paris was the lead author.

Fifty-week, updated results of ANRS 082 involving 70 participants (11% women) were presented. By week 24, the study arm taking IL-2 plus HAART revealed a significant CD4 cell count increase of 65 cells/mm3, compared with an increase of just 18 cells/mm3 for those who continued only HAART. Dr. Katlama reported that a significant proportion of the new CD4 cells were naive, or able to respond to new antigens or infections.

The dose of IL-2 was 4.5 million international units (MIU) self-injected twice daily for five days every six weeks: this cycle was repeated four times up to week 24. After that, IL-2 was allowed for all subjects. Then the dose was 9 MIU for five days every eight weeks. After 24 weeks, CD4 cell count increases in both study arms continued through week 50. The mean increase in CD4 cell counts was 0.12 cells/µL per day for subjects taking HAART alone, compared with 0.54 cells/µL per day while taking HAART with IL-2. Extrapolating from these results, Dr. Katlama calculated that the time to reach a CD4 cell count of 250 cells/mm3 was three years while not taking IL-2 and six months while taking IL-2. There were only transient minor increases in viral load, which returned to baseline in most people. Adverse events during the five days of IL-2 were standard, with very high rates of flu-like symptoms.

Other researchers reported using IL-2 plus HAART or HAART alone in persons with a similar profile, but using a much lower IL-2 dose that was daily and continuous. Jay Lalezari, M.D., of Quest Clinical Research in San Francisco reported using IL-2 at a dose of 1.2 MIU/m2 daily for six months plus HAART or HAART alone in 115 persons (Study MA-9801). After six months, the IL-2 arm had a CD4 cell count increase of 61 cells/mm3, compared with the arm not taking IL-2, which had an increase of 35 cells/mm3. Even though these results were not statistically significant, the percentage CD4 cell count increase -- 4% in the IL-2 arm versus 1% in the arm without IL-2 -- was significant.

Moreover, Dr. Lalezari found significant increases in the natural killer lymphocytes (NK cells) of 157 cells/mm3 in the IL-2 plus HAART arm, compared with 20 cells/mm3 in the HAART alone arm. (NK cells respond to new antigens without prior immune exposure or "priming.") Lower IL-2 dosing was better tolerated and caused much less severe side effects. Dr. Lalezari commented that one of the subjects with refractory (treatment-resistant) hand warts saw them resolve after adding low-dose IL-2 to his HAART regimen. It appears that for those persons who do not derive a significant CD4 cell count increase from HAART even with an undetectable viral load, adding IL-2 may lead to CD4 cell count improvements.

Back to the SFAF BETA Spring, 2000 contents page.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.