8th Annual Retrovirus Conference
Section written by Graeme Moyle, MD, MBBS, with selected contributions by Harvey S. Bartnof, MD, Jules Levin, and Nancy Shulman, MD.
US Treatment Guidelines
The updated (February 2001) DHHS (US Department of Health and Human Services) HIV Treatment Guidelines were posted on the Internet during the Conference (www.hivatis.org) and were alluded to at several points during the Conference. The main difference in the revision is a more conservative cut-off in laboratory values in recommending anti-HIV therapy. For any HIV positive adult or adolescent with a CD4 count greater than 350 cells per microliter and HIV RNA greater than 30,000 copies per milliliter (bDNA test, Chiron/Bayer Quantiplex) or 55,000 copies per milliliter (RT-PCR, Roche Amplicor), "some experts would recommend therapy". With a viral load less than that level and a CD4 count greater than 350 cells, the new Guidelines recommend deferring therapy and observing with regular lab testing. The decision about when to begin therapy is very much an individual decision based upon a patient's own circumstances and preferences, with the physicians input. Oftentimes, a fully informed discussion between patient and physician is key.
Also, among other changes, there are additions to the list of "Strongly Recommended" PI (protease inhibitor) drugs. The additions include 3 "boosted" PI regimens, low dose ritonavir (RTV, Norvir) with either saquinavir (SQV, Fortovase or Invirase), indinavir (IDV, Crixivan) or lopinavir (LPV, combined formulation tablets Kaletra). Further efforts to compare the combinations most widely used were reported during the 8th Annual Retrovirus Conference.
the NRTI Drug Combinations Different as Backbones?
Studies from the dual therapy era (pre-HAART) suggested that, at least for the most widely used (and DHHS recommended) NRTI "backbone" regimens of zidovudine (ZDV, AZT, Retrovir) or stavudine (d4T, Zerit) plus either didanosine (ddI, Videx) or lamivudine (3TC, Epivir), the answer was no difference. Thus, the choice between these 4 NRTI backbones would be made based upon the following issues: (1) impact of future treatment options via drug resistance; (2) frequency and severity of adverse (side) effects; (3) potential impact on body shape changes; and (4) convenience of dosing with the third HAART drug in the regimen. Evidence to clearly inform these debates are limited, but each approach has its pros and cons.
Data regarding body shape, for example, vary between studies. In 131 patients who have only received ZDV or d4T backbones, one study by Dr. R. Rubio of Madrid, Spain found similar rates of fat loss and fat accumulation between these drugs (abstract 646). However, only 10 AZT patients and 16 d4T patients developed abnormalities, and the analysis by drug was not subdivided into fat loss and accumulation. Also, only 11% were taking NRTI drugs without a PI or NNRTI drug. By contrast, in a "cross-sectional" survey of 96 of 170 subjects randomized to d4T versus ZDV based regimens (in combination with 3TC plus IDV), higher rates of lipoatrophy (fat loss) were found in those treated with d4T, according to Dr. V. Joly of Paris, France (abstract 539). The patients had substantial prior ZDV (and/or ddI, ddC) experience and demonstrated similar efficacy and tolerability between the ZDV and d4T arms. The reasons for the differences between these 2 studies remain unclear, and could relate to methodological issues. However, this raises the question as to whether prior ZDV (or other NRTI drug) use predisposes d4T recipients to lipoatrophy. Overall, there have been several cross-sectional studies that have found a significant association (that does not necessarily mean causes) between d4T-containing regimens and lipoatrophy. See additional review of this study in the Lipodystrophy Section.
Evaluating treatment-naïve (no previous treatment) patients in the START studies allowed for comparing the efficacy of different dual NRTI drugs: ZDV/3TC (206 patients); d4T/3TC (101 patients); and d4T/ddI chewable tablets (102 patients), all with IDV as the PI drug (abstract 314). Robert Murphy, MD of Northwestern University in Chicago, Illinois reported that the median baseline viral loads (VL) and CD4 counts were 4.5 log (34,000) copies per milliliter and 407 cells per microliter, respectively, and were similar between groups. At week 72, the proportions of available patients remaining on initial therapy with an undetectable viral load (limit 500 copies per milliliter) were for 72% (ZDV/3TC, 48 of 67), 69% (d4T/ddI, 24 of 35), and 80% (d4T/3TC, 35 of 44) with no significant difference between groups. This suggests that these backbone dual NRTI drug combinations each provide similar antiviral efficacy.
"Enteric Coated" Beadlets
The main drawbacks to didanosine (ddI, Videx, NRTI drug) chewable tablets had been: (1) the gastrointestinal (GI, stomach-colon) side effects; (2) the need for separation from fat- and protein-containing meals (requiring an "empty stomach"); (3) the need to separate taking ddI with IDV and ketoconazole. The new and recently FDA-approved ddI "EC" (enteric coated) formulation can be taken with approved HIV medications including IDV and Ketoconazole. It appears as though the new ddI EC reduces GI side effects (see study below). The EC formulation prevents absorption in the stomach, allowing for absorption in the small intestine, thereby avoiding the need for "buffers" in the tablet formulation that increase GI side effects. There are still food restrictions when taking the new ddI EC: no food for 1/2 hour before taking ddI EC and for 1 hour after taking ddI EC. The manufacturer Bristol-Myers Squibb is testing this further in belief that the food-drug interaction (which reduces ddI exposure) may not be clinically significant, but the study is still ongoing. This may conflict with medications that have food requirements.
There were 2 presentations that showed equivalent potency with the new ddI-EC formulation. S. Shrader, MD of HCRN in Houston, Texas reported the results of a randomized trial of 138 treatment-naïve (no previous treatment) patients (14% women, 51% non-Caucasian) (abstract 318). They were randomized either to the older chewable tablet ddI formulation or the newer EC formulation, each once per day, in combination therapy with d4T (stavudine, Zerit, NRTI drug) and nelfinavir (NFV, Viracept, PI drug). The median baseline VL levels and CD4 counts in the 2 arms were similar (approximately 4.6 log copies per milliliter and 382 cells per microliter). The results after 48 weeks showed similar profiles of mean VL reductions, with a slightly larger decrease in EC recipients (-2.6 log for EC and -2.4 log copies per milliliter for tablets). CD4 increases were about the same in both groups (approximately 120 cells per microliter). The tolerability data indicated that significantly more subjects discontinued for adverse events from the tablet regimen (20%) compared with the EC regimen (7%), associated with somewhat lower rates of nausea and vomiting in the latter.
A separate trial of ddI-EC was presented by Joseph Gathe, MD of Houston, Texas (abstract 319). In the study, ddI-EC was combined with stavudine (d4T, Zerit, NRTI drug) and compared with zidovudine plus lamivudine (combination tablet of ZDV/3TC, NRTI drugs, Combivir). All patients also took nelfinavir (NFV, Viracept, PI drug) in an open-label, randomized study. Interim data from 333 of 511 treatment naïve subjects (28% women, 47% non-Caucasian) who completed therapy through 48 weeks were analyzed. The mean baseline CD4 count was 411 cells per microliter, with a VL of approximately 4.7 log (50,000) copies per milliliter. The interim results at week 48 showed that similar proportions of subjects on both regimens had an undetectable VL (limit 400 copies per milliliter, 57% ddI-EC/d4T, 55% Combivir) and with a lower limit of 50 copies per milliliter, approximately 37% in each arm. Median CD4 counts also increased similarly in both regimens (+156 cells in ddI-EC/d4T arm, +188 cells per microliter in Combivir arm). Discontinuation due to adverse events was similar in the 2 arms, 8-9%. The Combivir arm tended to have more nausea and vomiting, while the ddI-EC/d4T arm had more neuropathy (numbness, tingling in feet). As these two combinations appear similar in antiviral efficacy (although overall not as potent as other treatment combinations), the choice for each individual likely will be based on adverse events rates. Lipodystrophy (fat redistribution) events were not reported.
Tenofovir, efavirenz, and ddI are currently dosed once per day, and research is evaluating whether abacavir, 3TC, BMS-232632, FTC, and nevirapine might be dosed once daily
The number of regimens that are FDA-approved for (or have the potential for) once daily dosing is gradually increasing. Studies about emtricitabine (FTC, Coviracil, NRTI), tenofovir (PMPA, NtRTI drug) and BMS-232632 (experimental PI drug), each of which are dosed once daily, are included elsewhere in this newsletter. Both efavirenz (EFV, Sustiva, NNRTI drug) and didanosine (ddI, Videx, NRTI drug) are FDA-approved for once daily use (the new once-daily "EC" version of ddI is discussed in the previous report). Interest is growing in our understanding that 2 other NRTI drugs might safely be dosed once daily: lamivudine (3TC, Epivir) and abacavir (ABC, Ziagen). The long "half-life" of the activated "tri-phosphate" form (intra-cellular half-life) of each drug within immune cells (15 hours for 3TC and at least 12 hours for ABC) is the reason for the studies (abstract 746 for abacavir). Evaluating intra-cellular half-life is being done in research settings, but it still needs additional validity testing before it can be used commercially.
3TC 300 mg Once Daily. Dr. M. Sension of North Broward Hospital District in Fort Lauderdale, Florida reported the results of a 24-week comparison study, confirming the feasibility of once daily 3TC (abstract 317). This prospective (planned beforehand), randomized trial compared the efficacy and tolerability of switching to 3TC 300 mg once daily versus continuing standard dosing of 150 mg twice daily in patients with an undetectable VL (limit 400 copies per milliliter). The 3TC regimen must have been for at least 6 months, plus stavudine (d4T, Zerit, NRTI drug) and a PI drug (either indinavir [Crixivan] or nelfinavir [Viracept]. Among 81 patients (14% women), 78 completed the study. Not surprisingly, the results showed a high rate of maintaining VL suppression (limit 400 copies per milliliter) through 24 weeks for both regimens (95% once daily, 90% twice daily, by ITT analysis, including all enrolled patients). Using a lower limit of 50 copies per milliliter, 82% of subjects on the once daily regimen and 81% on the twice-daily regimen remained undetectable. No virologic failures (for some obscure reason defined as at least 1,265 copies per milliliter on 2 separate occasions at least 2-4 weeks apart) occurred. CD4 count increases were similar for both dosing regimens. Also, each dosing regimen was well tolerated with no drug-related serious adverse events reported.
FTC, EFV and ddI (7 pills once daily). J. M. Molina, MD of Saint-Louis Hospital in Paris, France reported the results of a triple combination of FTC, EFV and ddI (7 pills once daily at bedtime) in 40 treatment-naïve (no previous) patients (12% women). The median baseline HIV VL was 4.8 log (58,400) copies per milliliter, with a CD4 count of 373 cells per microliter in the open-label study. The interim results revealed that the once-daily regimen led to a 90% rate of VL undetectability (limit 400 copies per milliliter, strict ITT analysis, including all patients) after 64 weeks (abstract 321). Seven of 8 (88%) of patients with a baseline VL greater than 100,000 copies per milliliter achieved an undetectable VL. The overall undetectability rate for VL less than 50 copies per milliliter was not reported. The mean CD4 count increase was 219 cells per microliter. There was a 10% discontinuation rate, including 5% due to adverse events associated with ddI or EFV and the other 5% due to patient preference or lost-to-follow-up. Only one patient (2.5%) had virologic failure. There was a 15% rate of grade 3-4 adverse events in the first 24 weeks, with an 18% rate of new-onset adverse events during weeks 24-64. However, approximately half of each of those percentages was due to surgeries unrelated to study drugs.
3TC (300 mg), EFV and ddI, Once Daily. F. Maggiolo, MD of Bergamo General Hospital in Cremona, Italy presented the final, 48-week results of the once-daily regimen that combined 3TC (300 mg), EFV and ddI, and (abstract 320). A total of 75 treatment-naïve (no previous treatment) patients (21% women) enrolled in the prospective, open-label study. The median baseline CD4 count was 251 cells per microliter, with an HIV VL 5.1 log (123,000) copies per milliliter. Drug users represented 49%, 21% had a previous AIDS diagnosis and 41% were HCV positive. The regimen was administered by DOT for 17%. The results after 1 year revealed that 78% had an undetectable VL (limit 50 copies per milliliter, strict ITT analysis, all enrollees included). The CD4 count increased by a mean 199 cells per microliter. The percentage of VL undetectability was equivalent for those with a baseline VL greater or less than 100,000 copies per milliliter. However, the VL undetectability rate was 88% for those with a baseline CD4 count greater than 200 cells, versus 66% for those less than that (ITT analysis). The discontinuation rate was 20%, including 9% due to adverse events associated with study medications, 5% virologic "failure" with documented genotype resistance (K103N EFV in 1 and M184V 3TC in 4) and 4% due to non-adherence. The higher rate of virologic failure with drug resistance in the current study is noteworthy compared to previous study with FTC/ddI/EFV.
Amprenavir 1200 mg + Ritonavir 200 mg Once Daily. Two small reports indicated success with experimental, once daily, "boosted" dual PI drug combinations. R. Wood, MD of Somerset Hospital in Capetown, South Africa described 15 patients (33% women, 73% non-White) who took amprenavir (Agenerase, PI drug) 1,200 mg once daily with ritonavir (Norvir, PI drug) 200 mg once daily and the NRTI drugs 3TC plus abacavir (ABC, Ziagen) (abstract 332). Patients had been switched from the triple combination of APV/3TC/ABC (standard dosing) to the 1200/200 (APV/RTV) once daily dose or 600/100 (APV/RTV) twice daily dosing, with 89% having an undetectable HIV VL (limit 400 copies per milliliter) at the time of switch. The results after 12 weeks showed that 100% of those taking the once daily dosing (n=15) had <400 copies/ml (strict ITT analysis), and 72% (n=18) taking the 600/100 bid regimen had <400 copies/ml. At week 20, 91% of the patients (n=11) receiving the once daily had <400 copies/ml, and 100% (n=12) receiving the twice daily regimen had <400 copies/ml. The median CD4 count continued to increase during the same period. Combining RTV with APV improves the blood levels of APV. The once-daily regimen led to AUC drug level increases that were nearly 4-fold greater (total or "area-under-the-curve" concentration), trough (or lowest drug level concentration) levels more than 5-fold greater, and C-max (maximum peak levels) that were equivalent. Compared to blood levels for the standard APV dosing (1200 mg twice daily), the 600/100 mg twice daily regimen had reduced C-max, increased AUC by about 55%, and equivalent trough levels. New grade 2 (moderate) increases in liver enzymes developed in 7%, while new grade 2 increases in cholesterol developed in 13%. Mild-to-moderate vomiting, diarrhea and mouth tingling developed in 7% after the switch. While the 2 NRTI drugs were likely taken twice daily in the study, based upon information presented above, it might be possible that the 4-drug regimen APV/RTV/3TC/ABC could be taken once daily.
Concerns With Ritonavir Boosting Regimens including a NNRTI
Research by Dr. O. Degen of University Hospital in Hamburg, Germany confirms previous studies that there is a critical dose of ritonavir (RTV, Norvir, PI drug) needed with a "boosted" PI drug when the NNRTI drug efavirenz (EFV, Sustiva) or nevirapine (NVP, Viramune) is added (abstract 739). In these studies, RTV 100 mg twice daily was not enough to prevent a decrease in the boosted PI drug level. Whereas, when RTV 200 mg twice daily was used, the NNRTI drug did not affect the boosted PI drug level. Specifically, when efavirenz or nevirapine was added to amprenavAPV, Agenerase, PI drug) 450 mg and RTV 200 mg twice-daily in 12 patients receiving a concomitant NNRTI, the APV "Cmin" (minimum or lowest concentration) was not significantly reduced and concentrations were at least 3-fold above those observed with APV alone at standard dosing. However, in 5 patients receiving an NNRTI, the dose was changed to APV/RTV, 600 mg/100 mg twice-daily. Blood samples collected from 21 to 51 days after the switch demonstrated that the APV Cmin was decreased by approximately 80%. Despite the decrease, the median concentration was still higher than for APV alone.
1200mg + RTV 200 mg Once Daily
A report was presented by Jamal Suleiman, MD of Sao Paolo, Brazil using indinavir once daily (abstract 336). Merck Study 103/104 enrolled 40 treatment-naïve (no previous treatment) patients (47% women, 40% non-White) to take the 4-drug regimen of indinavir (IDV, Crixivan, PI drug) 1,200 mg once daily, RTV 200 mg once daily, and the NRTI drugs stavudine (d4T, Zerit) and 3TC, each twice daily. The median baseline HIV VL was 4.9 log (81,283) copies per milliliter, with a CD4 count of 329 cells per microliter. The results after 24 weeks revealed that 72% achieved an undetectable VL with a lower limit of 400 copies and 54% achieved an undetectable VL with a lower limit 50 copies per milliliter (both strict ITT analysis). Better results are hoped for, so Merck is expected to experiment with increased RTV dose to 400 mg combined with 1200 mg IDV. Grade 2-3 (moderate to severe) drug-related adverse events occurred among 15%, including hair loss, nausea, fever and stomach-area pain. Increases in fasting cholesterol that would have required treatment (greater than 240 mg per deciliter) occurred among 11% of 27 patients with baseline and 24-week levels. Kidney pain possibly associated with IDV developed in 1 patient. However, the premature discontinuation rate of 20% was mostly not due to adverse events.
There Efficacy Differences Between NNRTI Drugs?
Concerns regarding liver toxicity with nevirapine (NVP, Viramune, NNRTI drug) had been raised from Study FTC-302, see this section and this section). Another presentation at the Conference raised concern that this agent may also have lower efficacy relative to efavirenz (EFV, Sustiva, NNRTI drug) (abstract 324). Dr. Andrew N. Phillips of the Royal Free and University College in London, UK authored the report that was retrospective (study started and tabulated after events occurred). It included 2,203 patients (20% women) given their first NNRTI combination drug regimen with either NVP (1,325 patients) or EFV (878 patients). The study was derived from the large EuroSIDA cohort of patients. EuroSIDA is a clinic-based project that collects data from 64 clinics in Europe. Patients who began a regimen with NVP or EFV after July 1997 were studied. "Virologic failure" was defined as 2 consecutive HIV viral load (VL) measurements greater than 500 copies per milliliter, at least 6 months after starting the regimen. Baseline characteristics were similar with a viral load of 3.7 log (5,011) versus 3.9 log (7,943) copies per milliliter, for the EFV and NVP groups, respectively, and baseline CD4 cell count (269 cells vs. 266 cells per microliter, respectively). A prior AIDS diagnosis was slightly more common in EFV patients (41%) than in the NVP patients (34%). Only 5% of patients were naïve to (never took) any anti-HIV drugs (nearly identical in both arms), while greater than 57% had received at least 3 NRTI drugs and 30% had received at least 2 PI drugs.
The results were as follows. Follow-up included 920 "person-years" for NVP patients and 464 person-years for EFV patients. Virologic failure occurred among 30% for an overall rate of 0.5 per year. Factors significantly associated with clinical or virologic failure to the NNRTI drug regimen included: a higher number of previous NRTI or PI drugs; a lower CD4 cell count nadir (lowest level); a previous AIDS diagnosis; a higher baseline HIV VL; and number of NRTI drugs in the regimen. Virologic rebound at 12 months occurred in 48% of EFV and 65% of NVP patients. The chance of virological rebound or clinical progression was significantly lower with EFV regimens. The "relative hazard" (adjusted for baseline characteristics) of viral rebound for EFV regimens at 12 months was 0.57, representing a significant 43% lower chance of this event relative to NVP. For clinical progression (illness), the relative hazard was 0.49, a significant reduction of 51% of progression. It would have been helpful to see the results divided into those with and without hepatitis virus co-infection, by baseline drug resistance, and duration & amount of prior class-specific drug experience. Drug level monitoring, at least on a subset of patients, would have been helpful to assess adherence. Also, premature withdrawal rates would add some insight to the findings. A randomized comparison of these drugs in treatment-naïve patients is currently recruiting and may answer the issue as to relative efficacy of the 2 NNRTI drugs. A direct comparison in NRTI, PI experience patients, based on these data, is urgently warranted.
versus PI HAART in Initial Therapy
The DPC-006 study established efavirenz as a first-line NNRTI drug option, demonstrating superiority over standard indinavir (IDV, Crixivan, PI drug) dosing when either is combined with zidovudine (ZDV, Retrovir) and lamivudine (3TC, Epivir, both NRTI drugs). Dr. R. Levy presented longer-term (144-week) follow-up data (abstract 325). Only 8% of patients randomized to EFV failed to achieve viral suppression to less than 50 copies per milliliter in the study, with the rebound rate being 8% by 52 weeks and an additional 7% rebound between weeks 53 and 96. Whereas in the IDV arm, an incomplete suppression rate of approximately 16% and a rebound rate of 16% by week 52 occurred, with an additional 6% between weeks 52 and 96. After 96 weeks, with fewer patients available for analysis, rebound occurred in 3.5% of EFV and IDV patients. Using a mathematical model based on rebound rates in years 1 and 2, it was estimated that the median time to virologic rebound with the EFV+ZDV+3TC regimen would exceed 6 years. If the preliminary lower rate of rebound in year 3 were considered, it is possible this estimate of durability might have been longer, with a very favorable projection out to 10 years. But of course these are projections, and adherence must be good to achieve this. See NATAP website for more details.
Study: NVP vs NFV
The COMBINE Study compared nevirapine (NVP, Viramune, NNRTI drug) with nelfinavir (NFV, Viracept, PI drug), both dosed twice daily with zidovudine plus lamivudine (Combivir, NRTI double formulation tablet) (abstract 327). This was a randomized, open-label study of 142 treatment-naïve (no previous treatment) patients. Daniel Podzamczer, MD, PhD of Barcelona, Spain reported 36-week data. Baseline characteristics included a mean CD4 count of 359 cells per microliter and an HIV viral load (VL) of 4.8 log (60,255) copies per milliliter--about equal in both arms.
The results were as follows in the 36-week ITT analysis (all enrolled patients included). Using an ultrasensitive test (limit 20 copies per milliliter) and an ITT analysis, a significantly higher percentage in the NVP arm (67%) achieved VL undetectability than in the NFV arm (39%). The "on-treatment" analysis (excluding drop-outs) also revealed a significantly higher percentage in the NVP arm (80%) achieving undetectability than in the NFV arm (56%). There were significant numbers of discontinuations due to side effects in both treatment arms: 22% in the NVP arm and 19% in the NFV arm. This included discontinuations from NVP due to hepatotoxicity (liver toxicity) in 7% and from NFV due to GI (stomach-intestine symptoms) in 10%.
One difficulty with interpretation of the results of this study lies in modest baseline differences, which occurred by random chance, but may have favored the NVP arm. Approximately 40% in each arm were HIV-infected by IVDU. This might have affected adherence, since NFV adherence was less than that of NVP. After 1 month into the study, the 95% adherence rate was 59% for the NFV arm vs. 75% for the NVP arm, a significant difference. Also, transmission risk behaviors were different in the 2 arms. For example, the percentages of HIV transmission by heterosexual contact were 31% for NFV patients vs. 20% of NVP patients, while percentages of transmission by male-male sexual contact were 18% in NFV patients vs. 37% of NVP patients. Drug level testing among a selected subgroup of 15 NFV patients who had an undetectable viral load (limit 20 copies per milliliter) showed good blood levels, indicating an association between NFV adherence and viral undetectability. The rates of hepatitis virus co-infection for each arm were not presented, and this might have been different between the arms.
The combination of ritonavir (RTV, Norvir) with another PI drug is increasingly viewed as the best way to use this drug class. This leads to fewer daily pills and a boosted trough (lowest) level of the non-RTV drug. The key for Kaletra's success in suppressing viral load is the high blood levels achieved from the boost by RTV. Kaletra is a co-formulation of Lopinavir plus ritonavir in the same capsule. The benefits of potent viral suppression using the boosted PI approach must be balanced against the cost of (mostly) modest lipid increases (cholesterol and triglycerides or "fats"). Kaletra should be taken with food, as blood levels improve when dosed with food. There were five presentations at the Conference about Kaletra.
The key trial for the approval of Kaletra is a double-blind (drug type not known by patient or treating physician), randomized trial of twice-daily stavudine (d4T, Zerit, NRTI drug), lamivudine (3TC, Epivir, NRTI drug) plus either twice-daily Kaletra or 3-times daily nelfinavir (NFV, Viracept, PI drug, changed to twice daily after 24 weeks). The 653 patients essentially were naïve to (never took) anti-HIV therapy. The results showed superiority for the Kaletra arm over NFV, which became most evident at weeks 36 and 48. At 48 weeks, the HIV viral load (VL) was undetectable (limit 50 copies per milliliter) in 67% of patients in the Kaletra arm and 52% of those in the NFV arm, a significant difference.
The analysis presented at this Conference by Dr. M. King from Abbott looked at the time to treatment success defined as less than 50 copies/ml (abstract 329). The drawback of this analysis was that the 50-copy assay was not used on samples until week 24. At this time-point, approximately similar proportions, 65% in the Kaletra arm versus 60% in the NFV arm had an undetectable VL, an insignificant difference. However, among incomplete responders at week 24 (greater than 50 copies per milliliter) who remained on study, a significantly higher percentage of those in the Kaletra arm (88%) subsequently became undetectable, compared to only 41% of NFV patients. Consistent with a similar analysis from the DPC-006 study with EFV (see previous report), the total time to VL undetectability (limit 50 copies) was longer in patients with a baseline VL greater than 100,000 copies per milliliter. These results also show that some individuals take longer than 24 weeks to reach a VL less than 50 copies per milliliter.
Also, there was a difference between NFV and Kaletra in terms of achieving undetectability if baseline viral load was high (greater than 100,000 copies per milliliter). In the Kaletra arm, similar proportions of patients with a high baseline VL (84%) or a low baseline VL (less than 100,000 copies per milliliter, 85%) achieved undetectability. Whereas, in the NFV group, a significantly lower proportion of patients with a high baseline VL achieved undetectiability (60%) than those with a low baseline VL. Regarding adverse events, the rate of increased cholesterol (greater than 300 mg per deciliter) and increased triglycerides (greater than 750 mg per deciliter) was higher in the Kaletra arm than in the NFV arm. Interestingly, the rate of ALT elevation (liver enzyme) in people with HCV or HBV chronic infection was higher in the NFV than in the Kaletra arms, although it may not be statistically significant. An interesting new concept in predicting response to PI therapy called Virtual Inhibitory Quotient can be read in the Pharmacology section. Data on Kaletra resistance is also reported in the Drug Resistance Testing section. Additional information about safety, common adverse events, discontinuation rates, lipids, & hepatitis are detailed in the NATAP article ABT-378 vs Nelfinavir (+d4T/3TC
Triple NRTI Formulation
There were two randomized studies of Trizivir, the triple NRTI drug formulation of AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and ABC (abacavir, Ziagen). This 3-drug regimen means dosing of one pill twice daily, allowing for easy adherence. In one study, Margaret Fischl, MD of the University of Miami in Florida presented the 24-week interim results of Study ESS40005 (abstract 315). A total of 195 patients (25% women, 73% non-White) taking abacavir and AZT/3TC (as Combivir double NRTI drug formulation) for at least 16 weeks (with or without a PI and/or NNRTI drug) and <400 copies/ml (and CD4s >200) were randomized to continue their therapy or change the AZT/3TC and ABC to Trizivir. Patients were pre-stratified by use of Combivir/abacavir alone, or with PI or NNRTI. The preliminary results after 24 weeks showed that three patients (3%) had a viral load increase greater than 0.5 log (3-fold) increase over baseline: all were in the Combivir plus ABC arm with none in the Trizivir arm. The interim preliminary 24 week data suggests that Trizivir is comparable to Combivir+abacavir or possibly better, in terms of percent undetectable. The CD4 count increased by approximately 60 cells per microliter in both arms. Both regimens were well tolerated. This study is ongoing.
The second study was authored by Christine Katlama, MD of Hospital Pitie-Salpetriere in Paris, France (abstract 316). A total of 209 patients (19% women) on stable HAART were randomized to continue the same HAART regimen or switch to Trizivir, for the purpose of simplifying the therapy regimen. At baseline, the HAART regimen was 1 PI plus 2 NRTI drugs. The 24-week interim results showed that 6 patients had HIV VL rebound. Five of them were in the Trizivir arm, while the 6th was in the continued-HAART arm. However, 3 of the 5 in the Trizivir arm had had previous dual NRTI drug therapywith 2 of those 3 having either an intercurrent "heart attack" (myocardial infarction) or poor adherence with a suicide attempt. A 4th patient with rebound in the Trizivir arm developed intercurrent acute hepatitis A. The premature discontinuation due to adverse events was 12-13% in each arm. This study is ongoing. New resistance cut-offs were reported for abacavir & can be read in the Resistance Section.
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