PI Sparing For Initial or First

PI Sparing For Initial or First-line Therapy (also see Lisbon Late Breaker on NVP in high viral loads)

Atlantic Study: Nevirapine vs Indinavir vs 3TC Plus d4T/ddI for initial therapy. Rob Murphy presented preliminary 48-week data from the Atlantic Study as about 80% (n=235) of the 298 enrollees have completed 48 weeks and 61% (181) have 48-week viral load data available. This study compares IDV and NVP to a triple NRTI regimen and continues for 144 weeks in total. A lipodystrophy analysis is being conducted.

Nevirapine was administered 400 mg once daily after the dose lead-in of 200 mg. 3TC was taken 150 mg BID; indinavir was taken 800 mg TID. DDI was dosed once daily:

The baseline viral load is low and limits the interpretation of the data. The overall median baseline viral load of 4.36 (23,000 copies/ml) was a little bit higher here as more data is available than the 16,000 copies/ml that was reported at the Retrovirus Conference in February ’99. The median baseline viral loads for each treatment group were about the same. The baseline CD4s are about 447.

Only about 12% (28 of 235) overall had >100,000 copies/ml at baseline: 9 (11.4%) in the IDV group, 6 (8.5%) in the NVP group and 11 (12.9%) in the 3TC group. CD4s increased about 150 in each arm by 48 weeks.

Viral Load Results. After 48 weeks of follow-up using the ITT analysis, Murphy said that although there is no statistical significance between the arms in this table there is a suggestion of differences in the <50 analysis. There are about 55 persons in each arm (See Table 8):

Table 8. Viral Load Changes (ITT)
	<500 copies/ml	<50 copies/ml
IDV + ddI/d4T	59% (n=58)	57%
NVP + ddI/d4T	55% (n=55)	51%
3TC + ddI/d4T	57% (n=68)	49%

As-Treated Analysis (n=181). Again, although there is no statistical significance to the differences between treatment arms there is a trend for the 3TC arm to underperform in the <50 analysis (See Table 9):

Table 9. Viral Load Changes (As-treated)
	<500 copies/ml	<50 copies/ml
IDV + ddI/d4T	95%	90%
NVP + ddI/d4T	91%	82%
3TC + ddI/d4T	90%	78%

3TC Arm May Underperform in <50 Analysis When Viral Load is >51,000 copies/ml. The investigators did a post hoc analysis of viral load response for those above and below 51,000 copies/ml at baseline. Murphy said to remember that this still is a preliminary analysis and not all the data has been analyzed yet. There were no statitistically significant differences between the IDV and NVP arms whether by <500 or <50 copies/ml. But there was a trend approaching statistical significance (p-0.08) that the 3TC arm underperformed in the <50 group for individuals with >51,000 copies/ml at baseline (55% vs 31.6%). The reason this trend loses statistical significance could be because the number of people in this group was small.

Grade 3 & 4 Clinical Toxicities (related to study meds), Grade 3 & 4 Lab Abnormalities, and Study Discontinuations. There was a total of 57 (24%) study discontinuations: 20 in the IDV arm, 12 in the NVP arm and 25 in the 3TC arm. Discontinuations due to adverse events were 12 in the 3TC arm, 7 in IDV, and 5 NVP.

There were 6 cases (grades 3 & 4) reported for GI-related events in the IDV (n-79) and 3TC (n-85) arms (nausea, vomiting, diarrhea; and 0 in the NVP arm). There were 5 cases of grade 3 & 4 rashes reported in the NVP arm (n-71) and none in other arms. Four cases of kidney stones reported in the IDV arm (n-79). There were 3 cases reported for neurological toxicities in the NVP arm, 3 in the 3TC arm, and none in the IDV arm.

There were 4 cases of grade 3 & 4 elevated LFTs in the IDV arm, 9 in NVP arm, and 5 in 3TC arm. There were 7 cases of elevated y-GT in the NVP arm and one each in other arms. Elevated bilirubin—14 in IDV arm; elevated amylase—3, 3, and 6 in IDV, NVP and 3TC arms, respectively.

Mean baseline viral load 58,900 copies/ml; CD4s 332; 83% treatment-naive; all were NNRTI and 3TC naive.

Table 10. Viral Load & CD4 Changes
	OD<400 (n=99)	ITT <400 (n=145)	<50 OD	<50 ITT	CD4 Inc.
EFV+AZT/3TC	98%	67%	89%	60%	225
OD=observed data analysis; ITT is intent-to-treat analysis (non-completers=failure)

Although the d4T/3TC is considerably smaller than 006 (AZT/3TC) the results suggest that EFV/d4T/3TC may be more effective regimen possibly because d4T is easier to tolerate.

Abacavir vs Indinavir. Study 3005 compared abacavir + AZT/3TC to indinavir + AZT/3TC. Subjects were stratified by baseline viral load by >100,000 copies/ml or 10,000 to 100,000 copies/ml. After 16 weeks individuals were permitted to switch to open-label if viral load was >400 copies/ml on 2 consecutive occasions.

The study design may have affected compliance and some of the data outcome. All patients received 16 tablets per day (TID) to blind the participants from identifying which regimen they were on. In addition all were required to observe IDV eating and hydration requirements. However, the number of pills containing active drug was 4 in the triple NRTI arm (12 were placebo) and 12 in the indinavir arm (2 placebo). In real-life abacavir is a BID regimen and not affected by food intake.

At baseline the median viral load and CD4 was 70,795 copies/ml and 359 in the abacavir arm (n=282); 180 (64%) had between 10,000-100,000 copies/ml and 102 (36%) had >100,000 copies/ml. In the IDV arm the baseline parameters were about the same: baseline median viral load was 66,000 copies/ml, CD4s 360, 63% 10,000-100,000 copies/ml, 37% >100,000.

At week 48 the discontinuation rates were high at 38% in the abacavir arm and 41% in the IDV arm;17% (n=44) for adverse events in the abacavir arm, 21% (n=55) in the IDV arm for adverse events. Common adverse events leading to discontinuation-- nausea, fever, nausea & vomiting, malaise & fatigue, skin rashes, headaches. These include the symptoms of abacavir hypersensitivity. Study investigators report 19 potential (7.3%) abacavir related hypersensitivity cases: 11/19 were judged serious; 8 hospitalized; 1 person died after rechallenge.

Table 11. Abacavir vs. Indinavir
	AT <400	ITT <400	ITT <400 <100,000	ITT <400> 100,000	ITT <50 <100,000	ITT <50 >100,000
ABC	94%	51%	55-60%	55-60%	46%	31%
IDV	86%	51%	55-60%	55-60%	45%	45%
CD4 increases were about 142 for each group

In the subjects with >100,000 baseline HIV RNA, no differences were observed in the time to viral load rebound (to greater than 400, 1000, or 5000 copies/mL). At the GW symposium in Lisbon, Schlomo Staszewski showed data suggesting failure of IDV regimen results in higher rebound in VL for a number of individuals, while for a proportion of ABC failures VL may remain between 50-400. In the IDV arm 10% of persons reaching nadir viral load below 50 c/ml rebounded above 5000 c/ml at 48 weeks, while at week 48 90% with nadir above 400 c/ml rebounded virologically above 5000 c/ml. By week 8 70% with nadir above 400 had rebounded to over 5000. At week 48 of study 75% of those with nadir 50-400 had rebounded to above 5000. Compared to 75% rebound rate in IDV arm (50-400 nadir), 30% with VL nadir 50-400 rebounded by 48 weeks. Staszewski suggested the absence of significant rebound despite measurable viral replication may be specific for this regimen.

In a previously presented meta-analysis of 1488 individuals receiving NRTIs in 3TC studies; individuals with disease progression accumulated mainly in those with high viral load-low CD4 defined by above 5000 c/ml and below 200 CD4s. During observation period of 1 year "no relevant" disease progression occurred up to 5000 c/ml. Staszewski said this data allows hypothesis that VL levels up to 5000 c/ml may be tolerated without significant disease progression for a period of time. However, does a 3 NRTI regimen increase possibility for mitochondrial toxicity? It is not known. Will using a 3 NRTI regimen limit future treatment options with NRTIs?

MKC-442. Emivirine is a new NNRTI dosed twice daily. The purpose of this study was to compare antiviral activity, tolerability and safety of two doses of MKC-442 when given in combination with d4T+ddI. A second purpose is to examine the benefit of a 3 day dose escalation strategy to optimize initial tolerability.

203 NNRTI and PI naïve patients with limited experience (<28 days prior NRTI exposure) were randomized to 1 of 4 arms to receive 442 with d4T+ddI for 24 weeks:

Baseline: The median baseline VLs and CD4s were 21,000 copies/ml and 378 in the 500 mg arm, 33,000 and 343 in the 750 mg arm, 38,000 and 281 in the 250/750 arm, and 47,000 and 308 in the 375 in the 375/750 arm (See Table 12):

Table 12. Viral Load Changes
	500 mg bid	750 mg bid	250/750 mg bid	375/750 mg bid
Enrolled (n)	50	47	47	52
Week 24 ITT (missing = failure)
% <400 copies/ml	64%	57%	43%	52%
% < 50 copies/ml	54%	51%	30%	38%
Week 24 (observed data)
% < 400 copies/ml	73%	77%	53%	68%
% < 50 copies/ml	61%	69%	50%	50%

Adverse Events. The most common potentially MKC-442 related adverse events were headache, nausea, dizziness, and rash (majority grade 1). In the 750 mg arm 43% experienced grade 1/2 nausea, 47% grade 1/2 diarrhea, asthenia 34% (grade 1/2), 17% grade 1/2 vomiting. Investigators reported a transient grade 1/2 dizziness was experienced by 30% in this arm, and a 13% rate of grade 1/2 depression. 28% experienced a rash. Investigators reported the majority of these events were mild/moderate and transient in nature. They reported 99% of rash cases were grade 1 or 2, and the majority (83%) were treated through without interruption of MKC-442. There were 2 cases of grade 3 rash and no grade 4. 6% of patients discontinued MKC-442 due to an adverse event.

In the 500 mg bid arm 10% experienced a rash. For a number of patients, they experienced similar rates for the same adverse events as experienced in the 750 arm although the rates were a lower for some of them: diarrhea 25% grade1/2, headache 30% (grade 1/2), dizziness 18%. The authors concluded the 500 mg dose was better tolerated than the 750 mg dose. They concluded the lead in strategy did not improve overall tolerability compared to the 750 mg dose suggesting that a longer lead-in period may be warranted. A lead-in strategy using 500 mg bid for 14 days is being evaluated.

Grade 3/4 adverse events had low incidence rates. There were few reported grade 3/4 lab toxicities reported in 500 and 750 mg arms.

Interaction with Nelfinavir. After ICAAC, Triangle announced that in study # 303, in which nelfinavir was combined with MKC-442, they noticed unexpected interaction concerns between MKC-442 and nelfinavir. They had previously conducted a NFV-442 interaction study in healthy volunteers and found an interaction so the dose of nelfinavir was increased to 1000 mg tid in study 303. However, the interaction between the 2 drugs in 303 was more than anticipated and raises questions about combining MKC-442 with NFV and possibly other protease inhibitors.

MKC-442 Resistance Profile. In preliminary research, therapy-naïve patients were enrolled in two studies to receive MKC-442 with either d4T+3TC or d4T+ddI. Genotype rsistance testing was performed on all who experienced treatment failure. Resistance to MKC-442 was seen in 23 of 138 individuals. They saw resistance mutations not previously seen associated with NNRTI resistance

Further analysis showed viruses containing these unique mutations remained sensitive to other NNRTIs suggesting after a person failed MKC-442 they may be able to respond to a different NNRTI. However, data showed viruses containing the K103N were resistant to MKC-442, and this indicates that MKC-442 is unlikely to be effective after failing efavirenz. The K103N mutation is associated with EFV failure. It’s important to bear in mind that these studies were in vitro (conducted in the test tube) so are preliminary and inconclusive. But Triangle will conduct human trials to explore the possibilities that MKC-442 may be a useful first-line NNRTI because it may be salvageable in certain genotypic situations.

Three NRTIs as Initial Therapy: AZT+ddI+3TC. C Compagnon reported on this small open-label pilot study on behalf of the Community Hospital HIV studies Group Rothschild, Paris and Glaxo Wellcome. 26 individuals with HIV RNA above 10,000 copies/ml and 200 CD4s received Combivir (3TC 150mg+AZT 300mg) one pill bid + ddI 150 mg two pills once daily for 48 weeks. They used the Roche Amplicor Assay with a detection limit of 200 copies/ml and the analysis was Intent-to-Treat (ITT). As well, a Roche Ultra-sensitive below 20 copies/ml test was used. Missing data were replaced by last observation carried forward (LOCF), except in the case of early withdrawal. Patients who discontinued treatment were considered as failures. Statistical comparisons between adherence data and HIV RNA were performed using non-parametric Wilcoxon tests.

At baseline, patients had median viral load of 79,400 copies/ml (range 4.0 to 6.0 log), median CD4 of 504 (range 270-1449).

Of 8 individuals characterized as non-adherent by investigator’s opinion, 8 gave as reason missing 1 or more dose(s). None said size of pills. In some cases, study drug was stopped during a holiday or because of fatigue.

A concern about triple NRTI regimens that has been raised is the question of possible increased experience of mitochondrial toxicity. Continuing to follow a large set of patients for a prolonged period can address this question. Possibly a meta-analysis of all triple NRTIS study regimens could be performed in the future.

Pilot Open-Label Study of 3TC+AZT+Abacavir+Efavirenz. P. De Truchis, on behalf of the Francilienne Study Group, reported preliminary 24 week data from a small study of 31 treatment-naïve individuals who received this 4 drug PI-sparing regimen. Median baseline viral load and CD4 was 4.7 log (50,000 copies/ml; range 3.1- 6.2 log) and 322 (range 98-858), respectively.

At week 16, 25/25 evaluable patients had viral load below 400 copies/ml and 21/25 (84%) had below 50 copies/ml. Three patients modified their study drugs due to adverse events, 2 stopped efavirenz (dizziness), 1 stopped AZT (myostosis) and 1 stopped abacavir (mild isolated rash). Depression was reported for 2 patients without treatment discontinuation. At week 24, 94% (ITT, missing=failure) had below 50 copies/ml. ITT and as-treated at week 24 were about the same (ITT n=31, AT n=26). De Truchis said 26 patients were still receiving drugs at week 24, 96% had below 50 copies/ml, and two were considered failures: one lost to follow-up and 1 with 51 copies/ml at week 24. For patients with baseline viral load above 100,000 copies/ml (n=13) the median HIV-PCR reduction from baseline was 4 log (ITT, missing=locf), and for those with below 100,000 copies the reduction was 3.1 log (n=18).