Report on Selected Late Breakers at Lisbon European AIDS Conference

By Jules Levin, NATAP

In the final session today from 10:30 am to 12 noon, researchers reported late breakers.

1. Nevirapine in high viral loads
2. PMPA
3. Combination therapy in pregnant women and their newborns
4. Switching from PI to NVP Regimen in HIV+ Subjects under long-term successful treatment
5. Using therapeutic drug monitoring with genotypic testing to evaluate PI pharmacokinetics
6. IL-2 for those with low CD4s despite effective HAART

Lisbon is a pleasant and large city. I went into 2 pharmacies in Lisbon and asked if they carried HIV drugs. They both told me you can only get drugs at hospital. I met a doctor from Taiwan at the conference who told me that there are 2700 people with HIV in Taiwan. And that the government supplies HIV therapy for them. Tomorrow morning I head home.
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Nevirapine Antiviral Activity in High Viral Loads

Richard Pollard, from the University of Texas Medical Center, reported on a sub-study of a larger international study of about 2,200 patients (Boerhinger Ingelheim –1090 study). The larger study was a randomized, double-blind, phase III clinical endpoint study looking at AIDS progression events or death. In the larger study treatment-naïve and experienced patients were randomized to NVP with NRTIs including 3TC or NRTIs alone including 3TC.

The sub-study looked only at individuals who were treatment-naïve or had less than 28 days of any anti-retroviral therapy, They all received NVP+AZT/3TC or AZT/3TC with NVP placebo. In the sub-study they evaluated the NVP triple regimen in high viral load patients. About 80% of participants were from South Africa so about 55% were black and 41% white. Mean age was 35 years.

The sub-study is concerned with 154 more advanced patients: median 85 CD4s and 5.3 log viral load at baseline (194,000 copies/ml). In the NVP arm (n=74), 54% had above 100,000 copies/ml, 45% had above 200,000 and 32% had above 500,000. In the NVP placebo arm (n=80), 68% had above 100,000, 38% had above 250,000 and 23% had above 500,000. 58% (n=90) of patients had above 100,000 copies/ml, and 75% (n=115) had above 50,000.

The primary analysis looks at plasma HIV-RNA response. In the AZT/3TC alone group there was an initial viral load drop of about 2 log. By about 24 weeks the viral load increased to about 1 log below baseline and remained at that level out to 64 weeks. The NVP+AZT/3TC group had close to 3 log drop at week 16 and just over 2.5 log drop at week 64.

Response of those with High Baseline Viral Loads.
At week 48, the proportion of Patients below 50 copies/ml – ITT follows. The numbers were small for those above 500,000. 42% with below 100,000 (21/36) had below 50 copies/ml, and 17/38 (55%) with above 100,000 copies/ml had below 50 copies/ml at week 48.

About 50% in the NVP arm remained below 50 copies at week 64. Pollard said there was no statistical relationship at week 48 between baseline viral load and drop in viral load on therapy. CD4 increased about 120 in NVP arm after 1 year compared to 50 CD4 increase in AZT/3TC arm at 1 year.
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PMPA

Ian McGowan, from Gilead Sciences, reported data from study 902 in which PMPA (administered once daily) was simply added onto ongoing therapy for individuals. This data was previously reported at ICAAC in September. More details of this study are available on NATAP web site in ICAAC Highlights Reports.

He reported data first from study 901 which was a 4-week, placebo controlled, dose ranging study in treatment naïve and experienced patients.

Three doses were given: 75 mg, 150 mg, and 300 mg, all once daily. For the experienced group receiving the highest dose of 300 mg there was a –1.06 log reduction, while the treatment-naïve group experienced a –1.51 log reduction.

Three PMPA once daily doses were given: 75, 150, or 300 mg. The median time on study 902 is now 37 weeks with a range of 32-60 weeks. The patients had about 4.5 years of prior treatment experience. The mean baseline CD4 and viral load in the 300 mg dose arm (n=55) was 378 and 3.74 log (5,500 copies/ml). 91% were male.

Baseline NRTI Resistance (n=187) The study group was very treatment experienced. 6% of patients had no NRTI mutations at baseline. About 60% of patients had PI mutations. 35% had NNRTI mutations. 43% had high AZT resistance with 3TC resistance (M184V). 24% had high AZT resistance. 19% had low AZT resistance with the M184V (3TC) mutation.

Viral Load Response
There was a dose dependent response with a mean of 0.75 log drop in 300 mg group at week 24.

Over the course of the study they did not see a significant CD4 rise in any arms.

Nephrotoxicity.
The incidence of serious adverse events: 3/28 (11%) in placebo arm, 5/53 (9%) in 75 mg arm, 8/51 (16%) in 150 mg arm, 3/54 (6%) in 300 mg arm. Grade 1 creatinine toxicity is a rise above 0.5 mg/dL So far they have not observed any rises above 0.5 mg in serum creatinine in the 300 mg group except for a few fluctuations.
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Combination Therapy in Pregnant HIV-infected Women and Their Newborns

Katjia Wolf, from the University Children’s Hospital in Basel, reported on this study whose aim is to assess the safety of combination therapy in pregnant HIV infected women and their newborns.

Women received 2 or more anti-retroviral drugs and their newborns.

By October 1999, there were 103 pregnancies, 95 children born, and there is complete data on 85 mother-child pairs. 6 pregnancies are ongoing, there was 1 induced abortion, 1 extrauterine pregnancy.

About 40% of women diagnosed with HIV during pregnancy. Most women (67%) were at CDC stage A, 22% at stage B. During 1st trimester, 62 women had median viral load of 5000 copies/ml (3.7 log), 26% had below 400 copies/ml, and CD4 was 378. During 3rd trimester, 72 women had median viral load of 200 (2.3 log), 65% had below 400 copies/ml, and CD4 was 453.

The women were prone to use drugs which may effect newborns: i.v. drug use (5), methadone (6), cigarette smoking (22), alcohol (5), benzos/barbituates (3). Women were also receiving concomittant therapy: cotrimoxazole (13), antimycotics (10), antiemetics (6), psychotropes (3), ciprofloxacin (1), pentamidine (1), other (6).

At some time during pregnancy 100% were on NRTIs, 62% on PI therapy and 1% on hydroxyurea. During the first trimester 39% were on treatment and 26% on PI therapy. At delivery all were receiving treatment and 88% received i.v. AZT according to 076 protocol. One women received a single dose of NVP at delivery. Median viral load at delivery was 2.26 log (below 400 copies/ml in 64%).

Nelfinavir (27) was most commonly used PI: IDV (19), RTV (8), SQV (7). AZT and 3TC were used by 77, d4T (16), ddI (8), NVP (2).

Mild anemia was the most frequently experienced lab abnormality: grade 1 or 2 (n=81)- 15 on RTIs and 26 on RTIs + PIs. Other abnormalities, such as thrombopenia, LFT elevations, amylase elevation and cholesterol were generally not severe nor associated with clinical symptoms.

5Women were often suffering with nausea and vomiting or diarrhea. Neurological symptoms were also quite frequent, mostly headaches.

Most of children (86%) were delivered by elective C-section (primary 66% before onset of labor and rupture of membranes). 14% (n=12) had vaginal delivery.

Newborns (mean follow-up: 7.8 months (birth – 26 months) 92% received AZT suspension for 6 weeks; 5% for less than 6 weeks 9% had combination therapy: I recd single dose of NVP after birth; most recd double therapy none of children were breastfed13% recd concomitant treatment with mostly antibiotics

Anemia was most frequent lab abnormality in newborns. 7 babies had grade 3 anemia leading to withdrawal of AZT in one. 2 required transfusions. 18/39 babies experienced anemia in first week of life and 17 recd AZT in utero (10 RTIs, 8 RTIs+PI). 21/28 babies experienced anemia during weeks 2-4. 1 baby had thrombopenia and 2 with transient elevated LFTs.

Clinical Adverse Events for Newborns
As previously reported they found a high prematurity (<37 weeks) birth rate in this study (11 receiving RTIs and 13 receiving RTIs+PI). 6 experienced neurologic symptoms but 3 were on drug withdrawal.

*below 10th percentile in weight

So far there have been two perinatal transmissions. One was receiving AZT=3TC, had a vaginal delivery with 3077 copies/ml of viral load. The other was receiving AZT+3TC+NFV, had a secondary C-section and had 10,000 copies/ml viral load. Delivery was not optimal for these two women and both women had a detectable viral load. All other children have negative HIV test results at about 4 months.

Investigators compared prematurity rate of children in this study to those of the Swiss Neonatal HIV Study exposed to AZT only or to no HIV therapy at all and found it to be higher in children on combination therapy when compared to children receiving no therapy during pregnancy (p=0.001).

In summary, adverse events occurred in 72% of women but were not unexpected and were not life threatening. And in 55% of newborns with 3 unexpected findings: high prematurity rate, CNS hemorrhage in a term born baby, 1 case of extrahepatic biliary atresia. Wolf concluded there was no clear evidence of a major risk of intrauterine exposure to combination therapy. But there was a high rate of prematurity and 1 major malformation which demand further inquiry. Therefore, a long term observation of large group is necessary. When asked by panel what she thought a pregnant women should do in terms of treatment, Wolf said it should be women’s decision based on an informed consent about the risk of therapy and for her own health if she’s not taking combination therapy during pregnancy. If the patient asked for Wolf’s recommendation, she said she would recommend combination anti-retroviral therapy during pregnancy.
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Switching from PI to NVP Regimen in HIV+ Subjects under long-term successful treatment

There has been a good deal of discussion and abstracts at this conference on switching people from PI to non-PI regimens (either abacavir or NNRTI based triple regimens) in the hopes of alleviating metabolic complications, lipodystrophy syndrome, improving adherence, reducing pill burden, and improving quality of life. Several studies have been reported on switching people to a triple abacavir NRTI regimen or a NNRTI based regimen. In this study 138 patients were randomized to switch to NVP with the same NRTIs (n=104) or to continue with their current PI-containing regimen (n=34). They were on their PI regimen for more than 1 year, had above 200 CD4s, and had below 50 copies/ml for more than 6 months. All were NNRTI-naïve.

Prior exposure to PI therapy was about 17 months for both groups. Those in NVP group had 9.4 months below 50 copies/ml and those in PI group had 8.7 months below 50 copies/ml. CD4 count was not significantly different at baseline (640 in NVP group; 500 in PI group; CD4 % was 25 in NVP group and 22% in PI-group). Cholesterol and triglycerides were about the same in both groups ( 245 chol. and 290 trig.; about 75% in both groups had above 200 mg/dL chol.) About 60% in both groups had trig.above 200 mg/dL. And about 70% in both groups had lipodystrophic body-shape changes. There was an inversion of the HDL/LDL ratio.

Results
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. The difference was statistically significant. At the time of failure median values of viral load tended to be higher for those continuing on PI (54% on PI and 31% on NVP above 500 copies/ml). A higher incidence of poorer compliance was reported for those failing PI regimen (90% vs 22%). In 3/7 patients on NVP regimen they detected codon mutations to one of the drugs in combination. Two patients had NVP mutations and 1 with 3TC mutation. No resistance was detected in those failing PI regimen.

Those switching to NVP had a mean loss of 35 CD4s but those continuing on PI had mean increase in CD4s of 64 at 6 months.

A trend towards a reduction in both trig. and chol. (10-15%) was seen in both groups but there was no statistical significance. In the PI group 73% had chol above 200 at baseline and 64% at month 6. In the NVP group 77% had chol above 200 at baseline and 58% at month 6. Regarding trig., 61% in the PI group had above 200 at baseline and 47% at month 6. In the NVP group 57% had above 200 tig. at baseline and 45% at 6 months. None received lipid lowering drugs. But all were advised to follow a low-fat diet which could explain this observation.

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. Half of them reported some improvement in these features after 6 months switching to NVP. 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.

Using Therapeutic Drug Monitoring of PI Therapy and Genotypic Testing

Andrew Urban, from the University of Wisconsin at Madison, reported preliminary cross-sectional data from study looking at prospective use of 2 technologies—genotypic resistance testing and pharmacokinetic profiling in protease inhibitors in the management of HIV in their clinic population. Urban went on to say that the role of therapeutic drug monitoring is controversial for a number of reasons including the variability in PK parameters both among and between individuals, we don’t have established pharmacodynamic predictors of ART efficacy, certain drugs work in tissue compartments which are not readily accessible such as NNRTIs, protein binding plays a significant role in free drug concentrations amongst the protease inhibitors, and the logistic and practical difficulties of getting drug levels in the clinic setting.

Urban said despite these difficulties its becoming increasingly clear that pharmacokinetics of these drugs is playing an important role in the success of anti-retroviral therapy (ART).

This study consists of patients who are on an initial or first salvage PI HAART regimen. Virologically successful patients (n=17) have viral load below 500 copies/ml. These patients are undergoing prospective evaluation with clinical assessment, CD4s, viral loads, and PK monitoring. At the time of study entry they have a complete PK profile performed and prospectively in patients with sub-optimal PK they randomize patients to adjusted dose versus a fixed dose. Patients who are virologically failing (above 500 copies/ml; n=15) on at least two measurements a month apart. These patients also undergo a baseline PK profile and also genotypic resistance testing. Based on the results of these evaluation,s they have drugs altered in the regimen and/or PI dose adjusted and are also followed prospectively. The endpoints are durability of viral suppression in the success arm and in both arms change in HIV-RNA.

The PK profile is performed around the observed dose of the protease inhibitor. Patients are instructed to come to clinic and take their dose as they would at home. Timed samples are taken before the dose is administered and also at one half-hour, 1 hour, 2 hrs, and 4 hrs after taking the dose. Optimal PK is defined as plasma concentrations within or exceeding a targeted range. Sub-optimal is defined as below this range. They target the Cmin concentrations of protease inhibitors as the parameter to target in prospective parts of study.

The reference ranges they are using:

At baseline 17 individuals in success group were 43 (29-55) years old, 13/4 male/female, 5/17 had prior PI, 477 CD4s, and below 2.70 log viral load. The failure group of 15 persons were 41 years old (30-61), 14/1 male/female, 9/15 had prior PI, 304 CD4s, amd 3.66 log (4500 copies/ml) viral load. Patients have been on 0-6 NRTIs prior to this study. Mean duration of current PI in success group was about 79 weeks (18-130). Several individuals were taking other drugs which can affect p450: RTV/SQV, NVP, or FLU. Nine were on NFV regimen, 6 IDV, 2 SQV (1 combined with RTV; 1 person on 600 tid SQV). Some were taking NFV tid and some were taking FV bid. For the failure group, 8 were on NFV regimen (on tid and bid), 3 were on IDV (2 persons taking IDV 1200 q12h), 3 on SQV 1200 q12h and 1 person on RTV/SQV. Again, 9 persons in failure group were taking concomitant drugs effecting p450: DLV, EFV, NVP, FLU. Mean duration of PI use was 49 weeks (4-128).

In the failure group at baseline 87% had evidence of high-level resistance to at least one component of their HAART regimen. 40% had resistance to more than one.

Failure Group- Number of Patients with Baseline Genotypic Resistance Mutations

Pharmacokinetics
In the virologically successful group 65% had optimal PK (within Cmin ranges listed above) versus 21% in the virologic failure group. This was statistically significant. There is no statistically significant difference between the two groups when looking at Cmax with the successes having 53% and the failures 43% within the target ranges. In looking at failures with sub-optimal PK about half had evidence of primary protease mutations. In looking at group that had optimal PK but were virologically failing all had primary mutations to their protease inhibitor.

In looking at NFV PK parameters of succeses versus failures there is statistically significant difference in the Cmin. The number of patients on other PIs were too small to analyze. There was no statistical significant difference in AUC between 2 groups although successes had greater AUC than failures.

Urban concluded that PI therapeutic drug monitoring may have a role in the management of ARV therapy. Virological failures demonstrated evidence of sub-optimal PK and genotypic resistance. At least in the NFV patients optimal Cmin concentrations correlate with virologic success.
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IL-2 + HAART for Persons with Low CD4s Despite Effective HAART

Christine Katlama reported on study ANSR 082 which is a randomized comparitive open-label study in 19 centers in France of IL-2 in patients with CD4 below 200 despite effective HAART. Patients were included in this study if they had CD4 count between 50-200, if their viral load was below 1000 copies/ml, and on stable HAART for a minimum of 6 months.

Patients were randomized to IL-2 +HAART or no IL-2. The IL-2 was given sub-cutaneous 4.5 MIU bid in 4 cycles of 5 days every 6 weeks up to week 24. After 24 weeks IL-2 was given sc 9 MIU qd for 5 days every 8 weeks up to week 80. After week 24 IL-2 was offered to initial control group and if they still fit the inclusion criteria. 72 patients were randomized and 70 were evaluated. 31 patients in the IL-2 group completed the 24 weeks on IL-2. Three of 34 patients discontinued: 1 for adverse event, 1 wanted to stop, and 1 for progression to KS. Five patients reduced their dose.

After 24 weeks, 89% in the control group started IL-2 and 82% in IL-2 group continued with IL-2. 55% of patients in both groups had a prior AIDS defining event. They were all on mean duration of HAART for about 18 months. At initiation of HAART CD4 was about 65. After 6 months on HAART CD4s were 113 in IL-2 group and 89 in control group. At study entry CD4s were 149 in IL-2 group (n=34) and 138 in control group (n=36). The % with below 100 CD4s was 15% in the IL-2 group and 22% in the control group.

76% in the IL-2 group and 89% in the control group had below 200 copies/ml. 18% in the IL-2 group and 8% in the control group had 200-500 copies/ml. And, 6% in the IL-2 group and 3% in the control group had 500-1000 copies/ml.

Results
At week 24 by ITT analysis, there was a highly significant difference between the two groups. The median CD4 count was 220 in the IL-2 group (range 101-394) and 158 (30-281) in the control group. The median increase was 65 (12-228) in the IL-2 group and 18 (-60 to 107) in the control group. The % of patients with CD4 increase of at least 50 was 73% in the 1L-2 group and 22% in the control group. The % with at least an 80 CD4 increase was 41% in the IL-2 group and 3% in the control group.

During the study 6 in the IL-2 group and 2 in control group had transient rise in viral load above 1000 copies/ml. Within 1 or 2 evaluation points the viral load returned to below 1000.

There was a significant increase in the proliferation activity against CMV with 58% in the IL-2 group who became positive (30% at baseline) compared to 21% (44% at baseline) in the control group. There was no significant difference between the 2 groups at baseline and week 24 using PPD, tetanus and p24 Ag. There was no activity at baseline and week 24 against p24.

There was a significant higher rise both in memory cells (44 in IL-2 group versus 1 in control group) and naïve cells (27 IL-2 versus 5 in control). Nearly all patients experienced the expected IL-2 side effects: fever, fatigue, muscle pain, nausea, rhinitis, sweats, dry skin/mouth, rash, arthralgia, insomnia, headache. But there was only 1 discontinuation of IL-2 and 5 dose reductions. Over 90% experienced fever and fatigue.

Additional cycles of IL-2 may result in continued increases in CD4s.