I'm in London now having left Durban two days ago

Durban World AIDS Conference
July 9-14, Durban, South Africa
Reported by Jules Levin from London July 17

REPORT 27

I'm in London now having left Durban two days ago and I'm returning Wednesday to NYC Big Apple. In retrospect, neither Mbeki nor Mandela have records of accomplishing much regarding HIV in South Africa. Of course we're more concerned about the current status of dealing with HIV in South Africa, but neither rulers showed much leadership regarding HIV. I think under Mandela's presidency little was accomplished regarding HIV. In addition, Mandela was unwilling to state strong support for treatment access in his speech at the Conference closing ceremony, although he did express support for intervention in mother-to-child transmission. It's been suggested that Mbeki's government is concerned about the costs of supporting surviving orphans if mother-to-child treatment intervention is instituted. It also appears as though corruption in governments in Africa is not uncommon. Winnie Mandela, however, expressed strong support for treatment access in her speech at the community march & protest before the Conference began. All of this does not make for being encouraged. Still, although valuable time is lost and much suffering has already been incurred by HIV infected individuals in South Africa, let's see if Mbeki reverses his positions. It's suggested that he may have felt unable to publicly reverse his position so quckly at the Conference. And that he may be more willing to do so in the weeks or months just following the Conference when there is less scrutiny by the press and world.

Substitution of Efavirenz for Protease Inhibitor(s)

You already received a NATAP Report on switching studies presented in Durban (switching from a PI to a PI sparing regimen). This study was reported in the Late Breaker poster session on Thursday in Durban, so it wasn't included in the previous report.

In this study 97% of those switching to EFV were able to maintain there viral load <50 copies/ml. These were individuals who were likely to have been on their first-line regimen upon entering study although this was not mentioned in the poster. They were on their PI regimen for about 2 years and had 3 consecutive <50 copies/ml viral load measures before switching. So this group was well suppressed virologically and likely were adherent.

165 patients were randomized to continue on their protease inhibitor regimen or switch to efavirenz (600 mg once daily, 3 200 mg pills). The NRTIs were maintained. This was a multi-center open-label study whose objective was to see the effect of switching on the durability of viral suppression in individuals who had viral suppression <50 copies/ml on a PI regimen. Another objective was to evaluate the safety of EFV in combination with the agents in the substitution regimens. Individuals with prior EFV or other NNRTI treatment were excluded. The poster did not mention it, but I assume the PI regimen individuals were on when they entered this study was their first treatment experience. Patients had 3 consecutive, monthly plasma HIV RNA levels <50 copies/ml, while on a combination of PI(s) + 2 NRTIs. The mean duration of PI treatment was 23.4 (ą7.8) months in the EFV arm and 24.1 (ą7.0) months in the PI arm. There was a third arm in the study consisting of a substitution regimen of EFV + PI(s) which was discontinued because of poor acceptance by patients and investigators.

Plasma viral load levels were determined by the Roche Amplicor HIV-1 Monitor Ultrasensitive Assay, lower limit of detection 50 copies/ml. Virologic failure was defined as confirmed on two consecutive assays plasma viral load levels 50 copies/ml.

At baseline mean CD4s were about 500 in both arms (range 113-1319). Over 90% of participants were white. Over 80% were men. The PI(s) individuals were on in the EFV arm (n=69): IDV 64%, NFV 26%, RTV 4%, RTV/IDV 2%, RTV/SQV 2%. In the PI arm (n=65): IDV 60%, NFV 26%, RTV 12%, RTV/SQV (2%), RTV/IDV (0).

The NRTI combinations individuals were taking: AZT/3TC 49% in EFV arm, 46% in PI arm; d4T/3TC 36% in EFV arm, 26% in PI arm; d4T/ddI 7% in EFV arm, 5% in PT arm; AZT/ddI 3% in EFV arm, 0 in PI arm; ddI/3TC 3% in EFV arm, 1.5% in PI arm; ddC/3TC 0 in EFV arm and 1.5% in PI arm.

The poster explained study definitions--Results were reported by Intent-To-Treat analysis (ITT) and by Observed Data analysis. ITT (noncompleter=failure) was defined as patients who remained in the study and maintained viral suppression (did not meet criteria for virologic failure) at the time-point were considered successes. Patients who had confirmed virologic rebound, discontinued the study for any reason, or had missing data at the time-point for any reason were considered failures. In the Observed Data analysis, data from patients whose plasma viral load were available at the time-point analyzed. Missing information, regardless of the reason, was not accounted for in this analysis.

RESULTS BY WEEK 24

In the ITT analysis, 67/69 (97.1%) (n=69) in the efavirenz group had <50 copies/ml; 54/65 (83.1%) in the PI(s) arm had <50 copies/ml (statistically significant difference between groups, p=0.0076). Using the Observed Data analysis, 67/68 (98.5%) in the EFV group had <50 copies/ml; in the PI(s) arm, 54/58 (93.1%) had <50 copies/ml (no statistical significance, p>0.05).

The investigators compared cholesterol changes from baseline between the 2 groups. In the EFV arm, mean baseline cholesterol was 228 mg/dL (standard deviation 43), 244 (SD 41) at week 12, and 239 ( SD 45) at week 24. In the PI arm, mean baseline cholesterol was 210 (SD 45), 222 (SD 56) at week 12, and 220 (SD 51) at week 24. Increases in mean HDL concentration were significantly greater at week 24 in the EFV arm: in the EFV arm HDL (good cholesterol) was 45.7 mg/dL (SD 15.1) at baseline, 49.7 (SD 15.5) at week 12, and 49.0 (SD 13.8) at week 24; in the PI arm, HDL was 42.1 at baseline (SD 14), 43.2 (SD 15.6) at week 12, and 42.1 (SD 12.5) at week 24.

CNS related adverse experiences reported in the EFV arm (there was statistical significance between treatment groups for these adverse experiences): dizziness (29%); insomnia (18.8%), 7.7% reported in PI arm; dreaming abnormal (23.2%); vertigo (20.3%); depression (10.1%), 3.1% in PI arm and the difference in depression was not statistically significant; concentration impairment (10.1%).

CD4 counts were maintained in both groups --495 in EFV arm at week 24 and 554 in PI arm at week 24.

Increases in GGT concentration (compatible with hepatic enzyme induction) were greater in the EFV substitution group, although there were no clinically significant changes in mean AST or ALT levels for either group.