Closing Ceremonies Durban World AIDS Conference 2000
Thursday, July 14
Durban, South Africa
Reported by Jules Levin

Report 20

ATLANTIC STUDY  

In a different Durban report the results of BI 1090 show that study participants with high virals (>100,000) appear to respond as well as those with <100,000 viral load. And, study participants in BI 1090 had more advanced HIV than those in Atlantic as measured by CD4 & viral load. In the Atlantic Why is there a difference between Atlantic & BI 1090 results in individuals with high viral load? Here are a few thoughts. Study, reported below, the number of patients who had >56,000 copies/ml at baseline in the 48 week ITT analysis reported below was small. NVP and ddI were dosed once daily in Atlantic and twice daily in BI1090. The FDA recently recommended twice daily ddI dosing was preferable to once daily. It's possible twice daily NVP produces better NVP blood levels than once daily. The 2N study is being planned to explore the NVP blood levels question. A third possible explanation, the primary objective or endpoiint of Atlantic was the percent of individuals <50 and <400 copies/ml. The percent undetectable <56,000> copies/ml was a post-hoc (added onto study after it started) analysis. So the study was not initially designed to answer the question of the response rate for individuals with viral load >58,000 copies/ml. But, it's my understanding that the >100,000 copies/ml analysis in the efavirenz 006 study was also a post-hoc analysis.

Here is an excerpt from BI 1090:

--At 12 months 42% (n=79) (ITT analysis) had <50 copies/ml in the NVP arm (<0.01). The baseline viral loads were divided into 4 groups based on the baseline values for the purpose of analysis: <31,000, 31,000-104,000, 104,000 - 372,000, and >372,000 copies/ml. I don't think it's statistically significant and there are about 20 patients in each of the 4 viral load groups, but there were no differences in percent undetectable between <100,000 and >100,000 copies/ml. There was no trend that people did worse in high viral loads. In fact in the 104,000-372,000 group, individuals did better than in the 31,000-104,000 group--

This high-profiled study of treatment-naÔve individuals compares nevirapine, indinavir, and a triple NRTI regimen. Each of the 3 regimens contain d4T+ddI combined with either 3TC, nevirapine, or indinavir. So, it's a PI regimen vs a NNRTI nevirapine regimen vs a triple NRTI combination. 48 week data was presented here in Durban, and it differs from the 24 week data previously presented. As you will see in the data reported below in the group of patients with viral load >56,000 copies/ml at baseline nevirapine did not perform well in terms of percent <50 copies/ml at 1 year. However, yesterday in the data set reported from the BI 1090 study nevirapine in a 3-drug combination with AZT/3TC performed much better. I sent out an email detailing that data.

The Study

The Atlantic Study was designed to compare the safety, activity, and durability of d4T/ddI/3TC, d4T/ddI/nevirapine (NVP), and d4T,/ddI/indinavir (IDV). It's an open-label randomized comparative strategic study of 3 triple drug regimens. The total duration of the study is 144 weeks. The primary study objective was to assess the comparability of the 3 regimens investigated in reducing the serum HIV RNA load to undetectable levels. 298 patients were enrolled with asymptomatic HIV (CDC 1993 stage A). Standard dosages of drugs were used except for NVP and ddI, which were dosed once daily.

At baseline, those receiving indinavir regimen (n=100) had median CD4 of 417 (range 329-560), viral load of 4.28 log (I misplaced my calculator but 4.00 log is 10,000 copies/ml, so maybe 4.28 is 20-30,000 copies/ml), and 11 (11%) had >100,000 copies/ml at baseline. In the NVP arm (n=89) at baseline, median CD4 was 394, viral load 4.26 log, and 10 (11.2%) had >100,000 copies/ml. In the 3TC arm (n=109), median CD4 was 396, viral load 4.25 log, and 17 (15.6%) had >100,000 copies/ml. So, all three groups were relatively comparable in CD4s and viral load.

RESULTS

In the ITT analysis after 48 weeks:

• IDV-   49% <50 copies/ml (n=100)

• NVP-  49% <50 copies/ml (n=89)

• 3TC -  40% <50 copies/ml (n=109)

On Treatment (OT) Analysis:

• IDV- 92% <50 copies/ml (n=54)

• NVP- 82% <50 copies/ml (n=54)

• 3TC- 67%<50 copies/ml (n=66)

HIGHER VIRAL LOADS (>56,322 copies/ml)

The study used a cutoff of 56,322 to evaluate the response with higher viral loads. Among patients with a baseline HIV RNA >56,322 copies/ml (upper quartile range), more IDV patients had HIV rNA <50 copies/ml at week 48 compared to NVP and 3TC, although this was not statistically significant (ITT: 48%, 28%, and 26%, respectively, p=0.18; OT: 80%, 56%, 42%, respectively, p=0.08). No difference was found with 500 HIV RNA c/ml as the cutoff (OT: 80%, 78%, and 79%, respectively, p=0.99).

ITT Analysis Week 48; The number of patients in this analysis is relatively small:

• IDV-  48% <50 copies/ml (n=25)

• NVP-  28% <50 copies/ml (n=22)

• 3TC-  26% <50 copies/ml (n=27)

CD4s increased across all 3 groups about 120-150 from baseline to week 48.

CLINICAL TOXICITIES (excluding events unrelated to study drugs and events that occur in <5% of subjects)

They did not list the incidence of elevated liver enzymes. The previous report at ICAAC 1999 had 55-68 individuals in the analysis of each of the 3 arms and they reported the following incidence of liver enzyme elevations: There were 4 cases of grade 3 & 4 elevated LFTs in the IDV arm, 9 in NVP arm, and 5 in 3TC arm.