Switching from Pi to abacavir regimen: preliminary 16 week data

Lisbon Report Nine
Jules Levin, NATAP

1. Switching from Pi to abacavir regimen: preliminary 16 week data
2. Triple NRTI Initial Therapy--3TC+AZT+DDI: preliminary data

This report contains results reported at Lisbon on a study switching individuals with below 50 copies/ml from a PI to abacavir, and a second small open-label study (n=26) initiating therapy with 3 NRTIs (AZT+3TC+DDI).

Replacing Protease Inhibitor with Abacavir: Preliminary 16-Week Data

N Clumeck from the Hospital St. Pierre in Brussels, Belgium reported on preliminary study data at 16 weeks from CNA30017 which explored switching individuals to abacavir in place of their PI. 211 individuals were randomized in an open-label comparison to continue their PI+2 NRTIs regimen or to continue their 2 NRTIs plus abacavir in place of the PI. The objectives of the study are to compare long-term durability of antiviral response (48 weeks), plasma HIV-1 RNA and CD4 profiles, safety and tolerance, and quality of life. Treatment failure is defined as above 400 copies/ml on two consecutive occasions or premature discontinuation of study treatment for any reason.

Individuals had to have a minimum of 6 months prior duration on their current PI+2 NRTI regimen, HIV-RNA undetectable since the beginning of ART, and below 50 copies/ml at screening. 80% in the abacavir (ABC) arm and 78% in the PI arm had received ART for over 12 months prior to study entry: I’m assuming the PI regimen people were taking at study entry was their first treatment, and that they were treatment-naive previously. I did not see this question addressed in the presentation or abstract. Here is a list of drugs people were taking at prior to study:

NRTIs (%) ABC PI
AZT/3TC 61% 63%
D4T/3TC 26% 24%

PI (%)
IDV 64% 52%
NFV 11 17
RTV 9 7
RTV/SQV 5 14

At baseline median CD4s in both arms were about 505 (ranges varied from 70-1500); median triglycerides (mmol/l) were 1.68 in the ABC arm and 1.64 in the PI arm; median cholesterol (mmol/l) was 5.18 in ABC arm and 5.34 in PI arm. It appears that lipids testing were non-fasting.

Results—
105 were randomized to ABC and 106 to continue PI. 102 recd ABC treatment and 103 PI treatment. There were 3 discontinuations due to adverse event in the ABC arm and 2 in PI arm. There were 2 hypersensitivity reactions in the ABC arm. There were 2 virologic failures in each arm. One withdrew from the ABC arm and 3 in the PI arm. And 1 was lost to follow-up in the PI arm. In total, 6 in the ABC arm and 8 in the PI arm were considered treatment failures.

75% in the ABC arm and 57% in the PI arm experienced at least 1 adverse event. The most frequent adverse events were nausea (75% in ABC arm v 57% in PI arm), diarrhea (16% v 6%), headache (5% v 10%), and malaise & fatigue (14% v 5%). I think some aspects of this comparison may be unfair. Of course ABC has its own set of side effects and potential toxicity but people on PI regimen at baseline likely experienced side effects upon starting regimen which may subside or they may get used to them after a while on therapy.

Two persons in the ABC arm had grade 3/4 elevated triglycerides and 3 in the PI arm. The investigator did not say if these two had these elevations prior to switching. One person in PI arm had grade 3/4 elevated cholesterol and none in ABC arm. These were drawn non-fasting.

There was a trend for decreasing triglycerides and cholesterol at week 16 following the switch in the ABC arm. While it appeared on the slide graph that the lipids in the PI arm remained about the same. The CD4s at week 16 increased slightly in the PI arm but remained about the same in the ABC arm. Clumeck summarized that preliminary 16 week data suggest TRIG and CHOL may decrease from ABC switch and also incident to ABC switch are reduced pill burden (ABC is one pill twice daily; Glaxo is developing one pill containing both ABC and AZT/3TC), and low risk of drug-drug interactions. Although there are no differences at week 16 in virologic failures between the two groups I think it’s premature to assess that parameter at week 16.

As I’ve reported previously in Lisbon summaries (see Lisbon Reports on NATAP web site), there were a number of studies reported at Lisbon on switching individuals to a PI sparing from a PI regimen due to concerns about tolerability, adherence, side effects and toxicities related to protesases. Studies looked at people switching from PI regimens to NVP, EFV or ABC regimens. The study presenting data on people initiating therapy with 3 NRTIs—AZT+3TC+DDI is reported below. And of course the Atlantic Study reported preliminary 48 week data on a triple NRTI regimen of 3TC+d4T+DDI. In this study there was a trend for people with viral load above 50,000 at baseline to not have as high a proportion of patients in study below 50 copies/ml at week 48.

In a study on switching people from a PI to a NVP regimen, reported as a Late Breaker, and reported in detail in the Lisbon Reports on the NATAP web site, Barreiro reported (ITT analysis) 29% in the PI arm and 11% in the NVP arm experienced a virologic rebound to over 50 copies/ml at 6 months after half of patients switched to NVP and half remained on PI regimen. The difference was statistically significant. A higher incidence of poorer compliance was reported for those failing PI regimen (90% vs 22%).

Based on patient survey and physician examination, 72% had lipodystrophy features at baseline and 6 months later 50% in NVP group reported at least partial improvement while no one in PI group reported improvement. Barreiro reported the pill burden reduction had a positive impact on quality of life. Patients were asked to rate quality of life from 1 to 10. Mean scores were 4.4 for PI regimen and 9.1 for NVP regimen. One criticism leveled at this study and others is that there is no evidence using objective parameters showing reversal of fat wasting in the periphery, other than patient and doctor observation. In a number of NVP switching studies, apparently elevated CHOL and TRIG are reduced while the data is more mixed on switching to EFV. In most studies, TRIG do not decrease except in one study where it did decrease. The total CHOL doesn’t decrease although the good CHOL (HDL) goes up. Graham Moyle’s presentation on switching to EFV will be summarized and reported separately.

I think if a person is completely able to be compliant with a PI regimen it may not be advisable to switch to a PI-sparing regimen. But if there are concerns about compliance and tolerability, particularly high elevations in lipids, and pill burden the data suggests a PI-sparing regimen may be effective. Of course the person’s individual situation must be considered in making these decisions. Additional treatment interventions can be made: lipid lowering drugs can reduce elevations but you have to be cautious about drug-drug interactions between PI or NNRTI and lipid lowering drug; diet and exercise help some individuals reduce lipids and glucose, improve overall sense of well being, and can reduce weight and stomach fat; HGH may reduce fat depots such as stomach but do not appear to reverse fat wasting in periphery. HGH can increase glucose.

This Sunday’s NATAP radio show focuses on lipodystrophy. The guests are Michael Dube of USC, and Joep Lange of the University of Amsterdam. The show is 11 pm to 12 midnight every Sunday on WOR 710 AM.. Free live audio and free RealAudio is available on the WOR web site—www.WOR710.com Free tapes of shows are available through NATAP.

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).

Results-
67% (ITT) had below 200 copies/ml at week 48(n=30); in the Atlantic Study one arm received 3TC+d4T+DDI and 57% (ITT) had below 500 copies/ml and 49% had below 50 copies/ml at week 48 47% (ITT) had below 20 copies/ml at week 48; at week 36, 60% had below 20 copies/ml. But this study did not report data on people with high HIV RNA, such as above 100,000 copies/ml at baseline median viral load reduction was 3.2 log at week 48 median CD4 increase was 169 at week 48 patients who were classified as adherent had a statistically significant greater viral load reduction at week 48 than those who were classified as non-adherent (aprx. 2.75 log v 3.25 log) 83% (n=25) experienced at least 1 adverse event 43% (n=13) experienced at least 1 drug related adverse event the most common frequent drug-related adverse events were nausea and vomiting (27%), leucopenia (20%), abnormal liver function tests (13%) of the 7 serious adverse events, 1 was considered drug related, a severe anemia occurred at week 16 that led to stopping study treatment. Two others permanently stopped study treatment because of non-serious adverse events: 1 for anemia, and leuconeutropenia, and one for nausea

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.