Durban World AIDS Conference
Wednesday, July 12
Durban, South Africa
Reported by Jules Levin

Report 17

Today, DuPont Pharma reported on 2 new protease inhibitors which may be effective for some individuals with PI resistance. The company expects to enter it's first human study soon. They also presented data on their new NNRTIs DPC 961 and 083. DPC 961 was initialy researched and placed on hold while they research 083, which has a halflife of 140 hours. Both of these NNRTIs are hoped to be effective for individuals with NNRTI experience & resistance. For comparison purposes efavienz is taken once daily but has a half-life of 55 hours, so 083 with a halflife opens up ideas. It will likely still be dosed once daily because it may be more effective overall than if dosed every 2 days. A human phase 2 study is expected to start soon.

This afternoon several studies of interest were presented in the Clinical Trials of Antiretroviral Therapy oral session.

Efavirenz+d4T+ddI+hydroxyurea

The first study was EFV+D4T+DDI vs the same regimen + hydroxyurea in both treatment naÔve & experienced. They used a high dose of hyroxyurea (HU) 600 mg BID while the usual dose is 500 mg BID. The HU arm did well but there were dropouts due to toxicities. A number of cases of peripheral neuropathy occurred in the naÔve arm although baseline CD4s were 350. As well, amylae and lipase were monitored and elevations were occurring, so these individuals stopped HU. However, the efficacy of the HU was looking promising. So Rob Murphy suggested that further studies should be done as HU may be useful in naÔve and experienced patients. Further details on the data will be reported.

Nevirapine in Treatment-NaÔve With High Viral Loads

BI 1090 was a prospective, double-blinded, placebo-controlled, multi-center-clinical endpoint study in naÔve and AZT experienced individuals with <200 CD4s. Patients received nevirapine +AZT/3TC or AZT/3TC. The Amplicor 1,5 Ultra-sensitive 50 copy Assay was used. The study was conducted in South Africa, Argentina and USA/Europe, but about 80% of patients were from South Africa, 58% were Black and 39% white in the NVP arm. There were 75 individuals in the NVP arm, and their median CD4 count was 87, and viral load 208,497 copies/ml (5.3 log). Using the 50 copy assay the median viral load reduction was about 3 log at about week 62 from baseline in the NVP arm. At 12 months 42% (n=79) 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, 31,00-104,000, 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. The 4 CD4 quartiles were <40, 40-95, 95-159, and >159. But CD4s were important in response. The two predictors for viral load failure were a person's baseline CD4 (<50 cells) and the viral load reduction at week 4 of study. Baseline viral load was not predictive of response. So  if a person had high viral load at week 4 after starting study they were not likely to respond to therapy.

Abacavir vs Nelfinavir + Combivir (AZT/3TC)

This is a 48 week open-label study comparing abacavir to nelfinavir 750 mg three times per day. This is a preliminary 24 week report. The study is to assess safety & tolerance (including metabolic complications. The primary endpoint of the study is the percentage of patients with HIV RNA <50 copies/ml at week 48. Individuals with viral load between 1000 - 500,000 copies/ml are eligible. There are 98 patients in the abacavir arm and 97 in the nelfinavir arm. The study had 3 analyses: (1) ITT Switch Included--switch of randomized medication not included as failure; (2) ITT switch=failure-- failure is change or permanently off randomized study medication, missing data, plasma HIV RNA >50 copies/ml, HIV RNA >400 copies/ml; (3) As Treated (AT): on treatment.   Median baseline viral load was the same in both arms--4.2 log (15,000 copies/ml) (range 1.3-5.3). Median baseline CD4s were 387 in abacavir arm and 449 in nelfinavir arm.

PATIENT DISPOSITION-- In the abacavir arm, 87 patients completed 24 weeks, 77 did not switch, 10 did switch, and 9 discontinued randomized treatment. In the nelfinavir arm, 83 patients completed 24 weeks, 74 did not switch therapy, 9 switched, and 9 discontinued randomized treatment. Of the 19 in the abacavir arm that made a treatment change, 13 were due to an adverse event, 5 withdrew consent, and 1 other. In the nelfinavir arm, there were 18 who changed their treatment: 11 due to adverse event, 2 withdrew consent and 5 other. VIRAL LOAD SUPPRESSION--at week 24 77% in the abacavir arm and 72% in the nelfinavir arm had <50 copies/ml (ITT Switch=Included). Using the ITT Switch=Failure analysis, 67% in the abacavir arm, and 66% in the nelfinavir arm had <50 copies/ml.  Using the As Treated analysis, 90% (n=72) in the abacavir arm and 86% (n=70) in the nelfinavir arm had <50 copies/ml. Both arms had a median viral load reduction of about 2.4 log at week 24.  The median CD4 change was about+90 in the abacavir arm and +65 in the nelfinavir arm at week 24. SAFETY & TOLERANCE--62% (110/188) had „1 adverse event. The most frequent („10%) drug related AEs were: nausea & vomiting 38% (n=36) in the abacavir arm, and 32% (n=29) in the nelfinavir arm; diarrhea--7% (7) in the abacavir arm and 41% (38) in the nelfinavir arm. 5% (9/188) had „1serious adverse events; there were 4 abacavir hypersensitivity reactions reported (4%). Early discontinuation of at least 1 study drug: 13 (14%) in abacavir arm, 11 (12%) in the nelfinavir arm. There was 1 serious AE in the nelfinavir arm and none in abacavir arm. COMMENTS: The baseline viral load was very low (4.2 log).

Previously, NATAP reported on this study: Dr Pedro Cahn reported in Durban that for individuals with >100,000 copies/ml at baseline at week 24 of this 48 week study, 66% of those receiving abacavir+combivir (n=58) and 54% of those receiving indinavir+combivir (n=65) had <400 copies/ml. However, he presented 55% taking abacavir+combivir and 45% taking indinavir+combivir had <50 copies/ml but he didn't specify how many individuals were in each of these <50 arms. So I reported the number of individuals in these arms that was reported in the program abstract which was about 20 in each arm. Since the conference, I've researched it further and it appears as though the numbers of individuals were the same as in the <400 analysis. The table below is modified using these updated numbers.

The preliminary 24-week data in this 48 week study reported on at Durban shows for individuals with HIV-RNA (viral load) above 100,000 copies/ml at baseline, 55% receiving abacavir+combivir (AZT/3TC) and 45% receiving indinavir+combivir (AZT/3TC) had <50 copies/ml.

Abacavir versus Indinavir In Combination with Combivir (AZT/3TC) in Therapy NaÔve (CNA3014): looks at baseline viral load >100,000 copies/ml

This is an open-label, randomized, multi-center 48 week study and Pedro Cahn from Buenos Aires reported preliminary 24 week data. The viral load endpoint is 400 copies/ml. The study looks at adherence, safety, tolerability, and "satisfaction". Patients have an option of switching therapy after week 16, if 2 consecutive viral loads are >400 copies/ml. Patients must have viral >5000 copies/ml and are stratified to viral load >5000 to 100,000 or >100,000. 342 treatment-naÔve individuals were randomized to receive abacavir/combivir (n=169) or indinavir/combivir (n=173). The two analyses used are Intent To Treat (Missing=Failure) ITT: all subjects taking at least 1 dose of study treatment; As Treated (AT): all subjects while on randomized treatment, with the exception of major protocol violators (pregnancy or non-adherence --cumulative total of >6 weeks or continuous of >2 weeks).  

There were about 60% men in each arm. Baseline median viral load was 4.8 in each arm (63,000 copies/ml). 64% in the abacavir arm and 62% in the indinavir arm were stratified to the 5,000-100,000 copies/ml group (n=216). 38% in the abacavir arm and 38% in the indinavir arm were stratified to the >100,000 copies/ml arm (n=126). CD4s at baseline were 323 in abacavir arm and 300 in the indinavir arm. 5 in the abacavir arm and 7 in the IDV arm did not start therapy. There were 14 (8%) discontinuations in the abacavir arm and 21 (12%) in the indinavir arm. Total subjects who changed therapy prior to week 24: 29 (18%) in the ABC arm, and 45 (27%) in the IDV arm. Here is the breakdown--Those who switched therapy due to viral load >400 copies/ml--4 in ABC arm and 15 in the IDV arm. Adverse event or lab abnormality: 6 in ABC arm and 7 in IDV arm. Listed as other reasons for switch of therapy: 17 in ABC arm, 23 in IDV arm. Using the ITT analysis 68% in the ABC arm had <400 copies/ml, and 57% in the IDV arm. Using the As Treated analysis, 87% in the ABC arm had <400 copies/ml and 83% had <400 copies/ml in the IDV arm. Over 100 were in each of these analyses.

Week 24 HIV RNA <400 c/ml in Stratification 5,000-100,000 copies/ml- ITT

Week 24 HIV RNA <400 c/ml Stratification >100,000 c/ml

Percent of Subjects HIV RNA <50 copies/ml  ITT--week 24

CD4s increased about the same in both groups--110.

ADHERENCE at WEEK 24

Took all doses: 58% in ABC, 25% in IDV arms

Took all doses or missed <1 dose per week: 74% in ABC and 45% in IDV arms. 

SUMMARY OF ADVERSE EVENTS

Any drug related AE: 59% in ABC and 75% in IDV arms

Any grade 3/4 AE: 4% in ABC and 12% in IDV arms

ABC hypersensitivity: 6%

AE resulting in study drug discontinuation: 9% in ABC and 10% in IDV arms.

Comments: It appears as though adherence and adverse events may play a role in the study.