Chelsea & Westminster Hospital.
Medical Consultant
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Issue 77 - Conference Report Special (Part 2) 39th ICAAC, San Francisco, USA
September 26-29, 1999 |
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CONFERENCE REPORT 39th ICAAC (Part 2)
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OTHER NEWS
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39th Interscience Conference on Antimicrobial Agents & Chemotherapy,San Francisco, USA. September 26-29, 1999 |
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Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI's)
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Schlomo Staszewski presented further results on two cohorts from DuPont Pharmaceuticals 006 study. The first 450 patients randomised had full 72 week data presented (initial cohort) and 1266 patients had data presented in a "duration of response" analysis (extended cohort).
Study 006 randomised patients to receive either efavirenz/zidovudine/lamivudine (EFV/ZDV/3TC), efavirenz/indinavir (EFV/IDV) or indinavir/zidovudine/lamivudine (IDV/ZDV/3TC), all given open-label in a multicentre, multinational trial. Subjects were all 3TC, NNRTI and PI na夫e, and 80% were completely na夫e to any prior antiretrovirals.
Previous data on the initial cohort to both 16 and 48 weeks was presented and reported in "Doctor Fax". This presentation on all 450 subjects to 72 weeks shows the previous results being confirmed and maintained. In an intent-to treat (noncompleter=failure) analysis at 72 weeks the following percentages of patients in each of the arms were below assay quantification limits for plasma HIV RNA (copies/mL):
| <400 | <50 | |
| EFV/ZDV/3TC | 67% | 60% |
| EFV/IDV | 49% | 46% |
| IDV/ZDV/3TC | 44% | 40% |
*difference between EFV/ZDV/3TC and IDV/ZDV/3TC at both <400 and <50, p(0.05 All arms showed similar CD4 cell count gains of around 200 cells/mm3 at 72 weeks.
Baseline mean plasma HIV RNA and CD4 cell count in the extended cohort of 1266 subjects was similar across the arms at 59,833 copies/mL (4.8 log) and 341 cells/mm3 respectively.
The "duration of response" data presentation for this extended cohort was a Kaplan Meier analysis of responders only (confirmed HIV RNA <400 copies/mL) with failure as the endpoint. Failure was reached when HIV RNA first reached (400 copies/mL (confirmed by second measure), AIDS or OI developed, or discontinuation for any other reason.
A significantly longer duration of treatment response was demonstrated for the EFV/ZDV/3TC arm in this analysis both when considering all patients and those with higher baseline viral loads (>100,000 copies/mL).
A separate poster presented preliminary 24 week results from study 044. This is a single arm open label study of EFV/d4T/ddI with similar inclusion criteria to the 006 study. Intent to treat analysis showed similar efficacy to the EFV/ZDV/3TC arm of the 006 study with regard to those achieving HIV RNA less than 50 copies/mL including subjects with baseline viral loads >100,000 copies/mL.
References: Staszewski et al. Longer time-to-treatment failure and durability of response with efavirenz + ZDV + 3TC: First analysis of full 1266 patient cohort from study 006. Stein A et al. Efficacy of efavirenz (EFV) in combination with stavudine (d4T) and didanosine (ddI) in antiretroviral therapy-na夫e HIV-infected patients (Study 044). 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1982.
Protease inhibitor containing regimens have now amassed considerable evidence for beneficial effects in the lymphatic tissues in addition to the more easily measured suppression of HIV RNA levels in plasma. To date, when compared to nucleoside analogue only regimens (including 3NA's), PI containing combinations have been shown to be more effective in suppressing virus replication and in both preserving and restoring structural integrity of lymphoid tissues. This superior performance of PI containing regimens in lymphoid tissues is observed even when compared to nucleoside analogue regimens with similar evidence for excellent suppression of viral replication obtained by measurement of plasma HIV RNA (both PI and non-PI subjects were suppressed to <50 copies/mL in plasma). It remains unclear if this effect is due to a superior HIV inhibition obtained with PI's or is specific to this class of drug due to some peculiarity of action associated with blocking of replication through specific inhibition of the protease enzyme (Ruiz L et al. 1999).
The NNRTI drug efavirenz is a potent antiretroviral which in combination with NA's has shown profound and durable plasma HIV RNA suppression comparable to PI containing regimens. New data presented at ICAAC as a late breaker also suggest profound suppression of HIV replication in lymphoid tissue with efavirenz containing combinations.
M Dybul from the US NIH presented data from a cross-sectional study of 9 patients being treated with efavirenz/stavudine/lamivudine (EFV/d4T/3TC) and 4 patients receiving either d4T/3TC or ZDV/3TC with either indinavir (n=2) or nelfinavir (n=2). After 7 to 8 months of therapy each patient underwent a lymph node biopsy. Mean pre-therapy viral load and CD4 count in the EFV group was 384,000 copies/mL and 451 cells/mm3 and 48,000 copies/mL and 388 cells/mm3 in the PI group. All subjects had plasma HIV RNA levels of <50 copies/mL at the time of biopsy.
In situ hybridisation for HIV RNA revealed one RNA producing cell in a germinal centre in two patients, one receiving EFV the other receiving a PI. Quantitation of HIV RNA in lymph node tissue using a NASBA assay showed that 6/8 in the EFV group and 3/4 in the PI group were below quantification (<100 copies). Co-culture assays found that 5/8 in the EFV group and 2/3 in the PI group had less than 1 cell per million expressing replication competent HIV.
References Ruiz L et al. Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue. AIDS 1999, 13:F1-F8. Dybul M et al. Evaluation of lymph node viral burden in HIV-infected individuals receiving an efavirenz-based protease inhibitor sparing HAART regimen. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-15.
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This study gives evidence that the impressive suppression of HIV RNA achievable with efavirenz based combinations and shown in plasma viral load assays is also mirrored by viral suppression in lymphoid tissue. Concerns remain however over qualitative immune system reconstitution with non-PI containing regimens. It is disappointing that this study missed the opportunity to present on lymph node architecture. It is unknown how long these subjects had been infected with HIV, and whether there were the pronounced immunopathological changes in lymph nodes associated with more advanced HIV-disease. Non-PI regimens must show equivalence to PI's in both qualitative as well as quantitative measures to convince on equivalence. |
Paul Blanchard, ATP.
The Virgo study is a multicentre open-label study conducted in France of the NNRTI nevirapine dosed either 400mg once daily or 200mg twice daily with d4T twice daily and ddI once daily.
Baseline characteristics of the first 100 patients enrolled include a mean HIV RNA and CD4 count of 4.7 log copies/mL and 432 cells/mm3 respectively. Results after week 24 are an extension study for those with >1.5 log copies/mL reduction in plasma HIV RNA or pVL <500 copies/mL. Francois Raffi presented the one year Virgo results during a poster session at ICAAC on behalf of the Virgo study team.
Due to the nature of the extension phase only on-treatment analysis could be reported beyond week 24. However, at week 24 the intent-to-treat (NC=F) analysis revealed that 74% of subjects had plasma HIV RNA below 500 copies/mL and 57% were below 50 copies/mL. At week 52 the on-treatment analysis gave figures of 84% of subjects <500 copies/mL and 62% of subjects <50 copies/mL (4 subjects had not reached 52 weeks and were excluded). These results are for the once daily and twice daily nevirapine arms combined.
The once daily regimen appeared to perform less well on the intent-to-treat (NC=F) analysis by about 10% less subjects below assay cut off. However, no statistical analysis of difference between the arms was presented. An approximate 200 cell/mm3 gain in CD4 cell count was seen at week 52.
Cutaneous rash due to nevirapine intolerance was seen in 24/100 patients but could be managed in most cases without stopping nevirapine. Longer-term suppression of plasma HIV RNA with this regimen will be tested by follow-up to 36 months.
Ref: Raffi F et al. d4T + qd ddI + nevirapine (bid or qd) in antiretroviral-na夫e HIV-1 infected patients: one year results of the VIRGO study. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1978.
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It is unfortunate that this is a non-comparative study and was only planned for 24 weeks. A comparative trial of nevirapine vs. efavirenz vs. the dual NNRTI combination is planned. |
Paul Blanchard, ATP.
The ability of a given combination regimen to provide durable suppression of viral replication has previously been shown to be related to the nadir obtainable after introduction of the combination to a patient. The reduction of plasma HIV RNA to less than 20 copies/mL has been shown in a number of studies to be a predictor of durable, maintained suppression when compared to only reaching a nadir of less than 400 copies/mL but above 20 copies.
It has been postulated that an additional contributor to durability may be the number of mutations required by HIV to become resistant to a particular drug. Those compounds requiring multiple mutations are said to have a higher genetic barrier to resistance. Viral replication would then have to be ongoing for a longer time period to enable the hurdling of this barrier and escape of drug resistant HIV. When only a single mutation is required for high level resistance this can emerge rapidly. Such is the case with the M184V mutation giving resistance to the nucleoside analogue 3TC. Indeed, the emergence of virus with this single mutation while treating with combination therapy containing 3TC may be the first sign of impending virologic failure of that regimen. Other antiretrovirals such as the protease inhibitors require a number of mutations to accumulate before high level resistance emerges. NNRTI's are closer to 3TC in this respect with all NNRTI compounds currently available requiring only a single HIV mutation before resistance is acquired. Unfortunately it is the same single mutation which gives cross resistance to this whole class of drugs (usually K103N).
Julio Montaner and colleagues explored the hypotheses that NNRTI based regimens might be more brittle than PI based regimens by comparing durability of viral load suppression across three clinical trials. 151 patients on triple therapy were included in the analysis from the INCAS trial (NVP/ZDV/ddI), AVANTI 2 (IDV/ZDV/3TC) and AVANTI 3 (NFV/ZDV/3TC).
After controlling for baseline viral load, CD4 and adherence with a proportional hazards model there were found to be statistically significant differences between the nevirapine triple combination trial arm and both of the PI based triple combination trials arms. This difference was only seen for those participants whose viral load nadir was between 20 and 400 copies/mL. Those on nevirapine with this strata of viral load nadir were found to have significantly shorter time that their viral load remained below 500 copies/mL, below 1000 copies/mL and lower than 1 log below their baseline viral load.
Montaner concluded that those patients who achieved a viral load nadir of between 20 and 400 copies/mL and receiving nevirapine had shorter virologic suppression than those assigned to indinavir or nelfinavir.
Ref: Montaner JSG et al. Patients with plasma viral load (pVL) nadir 20-400 copies/mL on ZDV/ddI/NVP have shorter virologic suppression than patients on ZDV/3TC/Indinavir or ZDV/3TC/Nelfinavir. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1992.
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Resistance data would be helpful on these patients, particularly now that phenotyping may be possible with samples of low HIV RNA (using the Phenosense test). Many questions are raised by this study and should be explored in further trial designs. Should NNRTI's be substituted with PI's unless less than 20 copies/mL is confirmed? Are other cautions needed if viral load takes a long time to go < 20 on NNRTI's, or gets stuck between 20 and 400? |
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Switching From Virologically Successful PI Regimens
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Steven G Deeks, MD. HIV InSite.
The concept of induction-maintenance therapy for HIV, in which a standard HAART regimen is followed by a less potent regimen, is of interest because of the adverse effects, high pill burden, and dose-scheduling difficulties associated with protease inhibitor-based regimens. To date, however, studies of induction-maintenance therapy have shown this approach to be ineffective.
There is a distinct difference between induction/maintenance and "simplification". The latter strategy involves switching patients from a complicated regimen (any indinavir based regimen for example) to a simpler regimen that has similar potency/efficacy. Several simplified maintenance regimens are actively being studied, including 2 nucleoside analogues and either abacavir or an NNRTI.
Opravil and colleagues conducted a study in Switzerland and Italy that used a simplified HAART regimen based on abacavir as maintenance therapy. The study enrolled participants with more than 6 months of therapy on a protease inhibitor-based regimen, HIV RNA below 50 copies/mL, and no mutations at codon 215 (associated with high level AZT resistance). Participants were randomised to either continue their current protease-inhibitor based regimen or change to a simplified regimen with a 4-pill daily total comprised of 300 mg abacavir twice daily and one Combivir tablet (300 mg AZT/150 mg 3TC) twice daily. Treatment failure was defined by an HIV RNA value of >400 copies m/L on 2 consecutive tests.
Virologic response was similar between the continuation and simplification arms, with 3 cases of virologic failure on the continuation arm and 5 cases on the simplification arm. CD4+ T cell counts were also comparable between arms. It is notable that in the simplification arm, there was a decrease in serum triglyceride and cholesterol levels, as well as an increase in HDL levels. This study suggests that a switch from a protease inhibitor-based regimen to a simplified abacavir-based regimen may preserve virologic response and reverse certain lipid abnormalities associated with protease inhibitor use.
Ref: Opravil M, Hirschel B, Lazzarin A, et al. Simplified maintenance therapy with abacavir + lamivudine + zidovudine in patients with long-term suppression of HIV-1 RNA. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 510. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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Switching patients from a complicated potent regimen to a simple potent regimen is straightforward and should work in most patients. However, clinicians need to consider what residual virus may be present before switching. For example, patients with prior zidovudine resistance (AZT) may do well on a protease inhibitor regimen (persistent HIV RNA < 50 copies/mL). When such patients later switch to a simple regimen such as AZT/3TC and abacavir, any residual resistance may become more important. In this Swiss study, investigators used sophisticated tests to examine cellular reservoirs for drug resistance. Since such tests are difficult to do in the clinic, these observations may not be generalisable to the clinic. |
Steven G Deeks, MD. HIV InSite.
The French Maintavir study prospectively enrolled 53 patients, all of whom met the following inclusion criteria:
All patients continued their nucleoside analogues and switched their protease inhibitor to either nevirapine (n=47) or efavirenz (n=6).
At baseline, patients had been a their PI for a median of 19.5 months and had a median CD4+ T cell count of 481 cells/mm3. Most (50/53) had a baseline HIV RNA < 50 copies/mL.
About half of the patients have had at least 6 months of clinical follow-up. Of the 53 patients enrolled, 7 eventually experienced virologic failure (4.6% failure rate at month 6). Notably, virologic failure was higher in patients who were on their second or third regimen at the time of study entry.
This study illustrates an important point: a patient's prior antiretroviral experience may be a marker of pre-existing drug resistance, even in patients with an undetectable HIV RNA. Switching such patients to a drug with a low "genetic barrier" could lead to rapid virologic failure. The investigators conclude that an NNRTI regimen can successfully replace a PI in patients who are unlikely to have any residual nucleoside analogue resistance.
Ref: Raffi F et al. Switch from PI to once daily NNRTI in HIV-infected patients maintaining undetectable plasma viral loads on PI-containing regimens: the Maintavir study. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 2198. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
Steven G Deeks, MD. HIV InSite.
A Spanish group led by Munoz and colleagues (Ramon y Cajal Hospital, Madrid) performed a similar nonrandomised prospective study on NNRTI-naive patients intolerant to protease inhibitors.[3] Patients were switched to either nevirapine (n=73) or efavirenz (n=43). As is common among European centres, prophylactic antihistamines were used in patients initiating nevirapine, to prevent rash. Of the 116 patients enrolled, 67% had an undetectable HIV RNA at the time of study entry (< 400 copies/mL).
As expected, adherence improved after the switch. Using > 95% adherence to define good adherence, 71% of patients on their protease inhibitor vs 90%-92% on nevirapine or efavirenz were considered to be adherent (P =.00001). Mean cholesterol and triglycerides levels decreased for both the nevirapine and efavirenz arms (P < .001). Approximately 85% of patients who had an undetectable HIV RNA at baseline maintained an undetectable HIV RNA 3 months after the switch.
Ref: Mu撲z V et al. Persistent viral suppression after switching a protease inhibitor (PI)-containing regimen to a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (BEGIN study). 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 2195. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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Switching from a PI-based to a PI-sparing regimen seems reasonable, but should be done with caution. These studies suggest that lipid profiles and adherence may improve after the switch. However, there is no clear evidence that fat redistribution ("lipodystrophy") improves with this strategy. More important, the risk of virologic failure after switching has not been defined. The French Maintavir study suggests that failure on the PI-sparing regimen may be common in patients who have a history of virologic failure on nucleoside analogues (and who might be expected to have residual nucleoside analogue resistance). |
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IMMUNOTHERAPEUTICS
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Howard Grossman, M.D. The Body.
This was a report of a randomised, double-blind, placebo-controlled study in advanced HIV infection. GM-CSF has been know to augment host immune responses. In vitro studies had found that GM-CSF increased HIV replication, but studies in humans have shown that GM-CSF decreases HIV replication (a warning about extrapolating in vivo assumptions from in vitro data!)
Patients were included who had <50 CD4 cells/mm3 or CD4 <100 cells with a previous opportunistic infection, stable antiviral therapy for at least 28 days and ANC >750 cells. Antiretroviral therapy was standard of care, chosen by the investigator. Subjects were stratified by viral load, above or below 30,000 copies/mm3.
GM-CSF was given at 250 mcg or placebo sc three times per week for 24 weeks. The investigator emphasised that this dose was not designed to augment neutrophil counts, since a much higher dose is usually used, but was, instead, intended to stimulate host immune response.
309 patients in 40 centres were studied. 70% completed 24 weeks. There was a large dropout rate and the speaker emphasised that this was not due to adverse experiences. He stated that patients either refused to start therapy or dropped out for other reasons.
Side effects were minimal. There were significantly more injection site reactions in the treatment group (25%) vs. the placebo group (4%) with a p value = 0.001. There was also more weight loss in the treatment group (18%) compared to placebo (10%), p=0.03. Both reactions were characterised as mild.
There was no decrease in clinical evolution, defined as an OI, bacterial pneumonia or death, but there was a delay in the median time to infection or death in the treatment arm.
| Placebo | Leukine | ||
| n=154 | n=155 | p value | |
| Any Clinical Evolution | 28 (18%) | 32 (21%) | 0.66 |
| Any Infection/Death | 120 (78%) | 104 (67%) | 0.03 |
| Median Time to Infection/Death | 56 days | 97 days | 0.04 |
CD4 counts were increased at every point studied in the leukine group (p=0.0004). There was no difference in viral load between the two groups.
50 patients entered the study with viral load <400 copies/mm3. Those on GM-CSF maintained undetectable viral load better and had a delayed time to changing antiviral therapy (a change allowed by protocol).
| Placebo | Leukine | |||
| n=28 | n=29 | |||
| Day 0 | 23 (82%) | 27 (93%) | p=0.65 | |
| Day 169 | 15 (54%) | 24 (83%) | p=0.02 |
The investigators concluded that Leukine, GM-CSF was well-tolerated and brought about a decreased time to infection or death, an increase in CD4 counts, delayed virologic breakthrough and delayed time to changing antiretroviral therapy. They suggest further studies using GM-CSF as an adjunctive therapy with HAART.
Ref: Angel JB et al. Randomised, double-blind, placebo-controlled study of Leukine (GM-CSF) in advanced HIV disease: significant improvements in overall infections, CD4 cell counts, and the duration of viral suppression. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 693. Report source: The Body: An AIDS and HIV Resource. See http://www.thebody.com
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G-CSF was previously shown to give a survival advantage to subjects with neutropaenia. It should be noted that in this study subjects had normal neutrophil counts. Cost would be a limiting factor for the adoption of GM-CSF at these protocol dosages (approx. ｣11,000 per patient per year). Further studies should investigate if the advantages seen in this study are maintained even if GM-CSF were stopped after CD4 counts rose above say 50 or 100 cells/mm3. |
Steven G Deeks, MD. HIV InSite.
The search for effective immune modulators for HIV disease is important because antiretroviral therapies have limitations for optimally controlling HIV over the long term. Recently, a large-scale study of Remune, a therapeutic injectable vaccine composed of inactivated gp120-depleted HIV-1, was stopped by its Data & Safety Monitoring Board when no difference in clinical progression or HIV RNA levels was detected between the treatment and placebo arms.
Kahn and colleagues enrolled 2,527 patients with CD4 counts between 300 and 550 cells/mm3 and no AIDS defining conditions (except KS) into a multicentre study comparing Remune to placebo. The average follow up time was 88.7 weeks. Local injection site reactions were the only significant adverse reactions observed. In the Remune treatment group, 44 patients experienced clinical disease progression, versus 46 in the placebo group. This was not statistically significant. Overall, the progression rate was 2.1 events per 100 person years of follow up. It was speculated that the effectiveness of HAART may have obscured any benefit derived from Remune. Ref: Kahn J et al. A randomised, placebo controlled multicenter study of Remune in subjects with 300-550 CD4 cells and unrestricted antiretroviral treatments. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-21. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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STOPPING HAART
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Paul Blanchard, ATP.
Much interest was generated at ICAAC by the preliminary report on 9 subjects stopping antiretrovirals after successful HAART plus daily low dose IL-2. Data on these subjects was presented by Dr Kendall Smiths group at Cornell University, New York. Dr Smiths group were the original discoverers of the IL-2 molecule in the late 1970's, and the IL-2 receptor in 1981.
Forty patients entered this study of daily, subcutaneous low dose rIL-2 in addition to HAART. IL-2 dosage was calculated by body area but was roughly equivalent to 2 MIU per day. Intermittent dosing protocols of IL-2 such as that used in the NIH studies use a dose of 15 MIU per day. The lower dosage in this study and the continued daily administration was chosen based on pharmacokinetic studies to be the maximum dose needed to saturate the IL-2 receptors on T-cells. At this dose IL-2 should not be associated with the systemic side effects seen with higher doses. Is systemic side effects were experienced the dose was lowered.
Fifteen subjects who followed the HAART plus low dose daily IL-2 protocol for one year entered a study electing to discontinue HAART, but to continue IL-2. So far nine individuals have suspended antiretroviral treatment. All subjects entered the study with chronic HIV-infection and CD4 counts of between 200 and 500 cells/mm3.
Plasma HIV RNA rebounded in all 9 subjects within two and a half to three weeks of stopping antiretrovirals. Over a further two weeks viral load then increased rapidly to a peak level (mean 350,000 copies/mL). Interestingly the viral load then fell rapidly for a further 2 weeks before settling at a level around 10% of the peak (mean 26,000 copies/mL). This 10-fold reduction occurred while subjects were still off antiretrovirals but continuing with the daily IL-2. The mean viral load before HAART was around 70,000 copies/mL, so this new level after discontinuation is also significantly lower than baseline (before any treatment). Five of the nine patients have since elected to restart antiretrovirals in consultation with their physicians. The other four are still off HAART, but receiving IL-2.
The investigators hypothesised that this type of IL-2 protocol may foster host immunity to HIV thereby reducing the speed and height of viral rebound on removing antiretrovirals. Continued low dose IL-2 while HIV antigen circulates with rebound may also facilitate expansion of CTL responses against the virus.
Ref: Jacobson EL et al. Restoration of immunity after HIV infection. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1828.
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An extensive interview with Dr Smith looking further at this study in the latest issue of AIDS Treatment News (ATN 329) available at: http://www.atn.org/atn |
Steven G Deeks, MD. HIV InSite.
For patients who begin HAART while in early infection, there has been speculation that discontinuation may be possible at some point without a rebound of plasma HIV RNA. Markowitz and colleagues from the Aaron Diamond Institute followed a cohort of patients who started HAART (AZT/3TC plus either indinavir or ritonavir) in early infection. Of the 14 patients who completed approximately 3 years on HAART, 4 self-selected to discontinue therapy. All 4 patients had started HAART within 60 days of primary infection. At the time of discontinuation, all had HIV RNA below 50 copies/mL and CD4+ T cell counts between 422-1306/mm3.
Following discontinuation, HIV RNA rose to detectable levels in all four patients after 14 to 26 days. One patient restarted therapy after 25 days. Viral load peaked at between approximately 14,000 - 22,000 copies/mL for the remaining three patients, although viraemia levelled off to between approximately 2,000 - 5,000 copies/mL after 5 to 7 months. A drop in CD4 percentage was also observed. Despite close to three years of "fully" suppressive therapy, all patients who opted to discontinue HAART had a rapid rise in HIV RNA, although viral rebound occurred later than in published studies of chronically infected patients. In addition, some control of HIV RNA seems to be maintained in these patients, at least in the short term, which the investigators hypothesise to be an immune-mediated effect.
The Aaron Diamond group recently published data on 6 patients who discontinued therapy. In this cohort, patients also had to have an undetectable HIV RNA on HAART. Two patients did not rebound (through 12 months for one patient and through 24 months for a second patient). Strong HIV-1 specific immunity was present at the time HAART was discontinued in the patients who remained suppressed off therapy (a limiting dilution assay to quantify HIV-1 specific cytotoxic T lymphocyte precursor frequency). Patients in this study received a protease inhibitor-based regimen during various stages of their infection (including primary infection).
Along similar lines, a group from the NIH presented early data from an ongoing prospective study entitled "NoHRT". In this single arm study, patients discontinue therapy and are followed closely. Inclusion criteria included: (1) HAART for > 12 months, (2) HIV RNA < 500 copies/mL for > 1 year, (3) HIV RNA < 50 copies/mL at screen and a (4) CD4 > 350 cells/mm3. This study enrolled many patients who had been on prior IL-2. Data from 18 patients was presented (12 had received prior IL-2).
At baseline, patients had a median CD4+ T cell count of 921/mm3, and had documentation of an undetectable HIV RNA for 108 weeks. Using sophisticated techniques, 3 patients had undetectable HIV using a highly sensitive nested gag PCR technique, one patient had no detectable HIV DNA and 7 patients had no detectable latently-infected CD4+ T cells. Despite the high levels of viral suppression achieved in this cohort, and the prior use of IL-2 (thought to perhaps help "flush out" viral reservoirs), virologic rebound occurred rapidly (usually within 2 weeks; the median time to a viral load > 500 was 18 days).
References Markowitz M et al. Virologic and immunologic profiles of newly infected individuals electing discontinuation of HAART after approximately three years of apparently suppressive therapy. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-16. Davey R et al. The NoHRT trial: a prospective study of cessation of HAART in HIV-infected patients after prolonged viral suppression. 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Abstract 689. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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With the exception of a few cases (the "Berlin" patient previously described and the 2 patients at the Aaron Diamond AIDS Center), virologic rebound occurs rapidly after drug discontinuation (in patients with an undetectable HIV RNA for 3 years or more). Other studies have suggested that resistance is not selected for in these studies, and that patients do well once therapy is restarted. Why some patients have limited or delayed rebounds remains to be determined, but all evidence is pointing toward the development and maintenance of strong and broad HIV-1 specific immunity. Efforts to boost immunity, either with controlled treatment interruptions or vaccines, are underway. |
Steven G Deeks, MD. HIV InSite.
There were few pathogenesis-oriented abstracts at this year's ICAAC. However, there was one provocative presentation during the late breaker session, which focused on the still unanswered question of how HIV causes CD4+ T cell depletion. There are those who believe that HIV causes disease by preventing CD4+ T cell production ("regenerative failure") and those who believe that the primary issue is accelerated destruction of mature T cells (along with an inability of the immune system to "keep up"). Although both mechanisms may be at play, this polarised debate continues to drive high quality research.
A group at the NIH evaluated T cell turnover in 67 healthy controls and 77 HIV infected patients. Peripheral blood mononuclear cells were obtained and labelled with bromodeoxyuridine (BrDU) ex vivo (for four hours) (actively dividing cells will incorporated BrDU). The percentage of CD4+ T cells taking up BrDU was 4 to 8 fold higher in HIV infected patients than HIV uninfected patients. Among HIV infected patients, there was a strong correlation between BrDU incorporation and viral load. These cross-sectional data suggest that HIV drives T cell production and destruction.
Eleven patients received a protease inhibitor-containing regimen and were followed longitudinally. As viral load decreased, there was a concurrent decrease in the percentage of CD4+ T cells that incorporated BrDU. Finally, 21 patients eventually stopped highly active antiretroviral therapy (the "NoHRT" study). To be eligible for this study, patients had to have had an undetectable viral load (< 500 copies RNA/mL) for at least one year, and a viral load < 50 copies/mL at baseline. After stopping therapy, all patients eventually rebounded (20 of 21 in the first few weeks). Coincident with the rebound in viraemia there was a dramatic increase in the percentage of CD4+ T cells incorporating BrDU. BrDU levels decreased when HAART was reinitiated.
Recognising the limitations of ex vivo labelling, a limited number of patients underwent infusion of BrDU (in vivo labelling). BrDU incorporation was determined at baseline and 12 weeks after initiating HAART. BrDU incorporation peaked at around day 5 and then rapidly decayed. The peak in BrDU incorporation (measured as % of CD4 cells labelled) was much lower 12 weeks after HAART (compared to pre-therapy)
The data are consistent with the hypothesis that viral replication drives CD4+ T cell activation, resulting in accelerated T cell destruction. CD4+ T cell depletion presumably occurs because the immune system is unable to continually replace these cells that actively turn over.
Ref: Lempicki RA et al. Impact of highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-14. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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NEWER ANTIRETROVIRALS IN DEVELOPMENT
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Steven G Deeks, MD. HIV InSite.
ABT-378 is a protease inhibitor currently undergoing phase III evaluation. A limited expanded access program has recently been announced. The drug should become widely available over the next year.
ABT-378 has limited oral bioavailability. It must be given with ritonavir (or other inhibitors of the cytochrome P450 system). The study medication is only provided with low dose ritonavir. According to the scientists at Abbott, when used in combination with ritonavir (at 100 to 200 mg bid), ABT-378 levels remain > 30-fold above the protein corrected IC 95 (12 hours after dosing). The drug has a promising resistance profile as well, although some common mutations (codon 84, for example) may compromise the drug's activity.
Two phase II studies are ongoing: M97-720 (treatment-naive patients) and M99-765 (early protease inhibitor failure). Data through week 36 of both studies were presented at the late breaker session. The drug appears to be well-tolerated. In 170 patients, there have only been 2 drug discontinuations for adverse events related to ABT-378.
Among treatment-naive patients, ABT-378/ritonavir, in combination with d4T and 3TC, resulted in impressive levels of viral suppression: 89% of patients were less than 50 copies/mL at week 36 (on-treatment analysis). Using an intent-to-treat analysis, approximately 75-80% of study participants had an undetectable HIV RNA at week 36 (< 50 copies/mL).
Despite these very impressive data among treatment-naive patients, the 36 week data in the salvage study are generating the most interest. In this study, NNRTI naive patients failing their first protease inhibitor containing regimen (viral load 1,000 to 100,000 copies/mL) received ABT-378 for 2 weeks, then modified their nucleoside analogues and added nevirapine. The mean viral load at study entry was low (about 10,000 copies/mL). Using an intent-to-treat analysis, 67% of patients had an undetectable HIV RNA (< 400 copies/mL) at week 36.
Ref: Eron, J et al. ABT-378/ritonavir (ABT-378/r) suppresses HIV RNA to <400 copies/mL in 95% of treatment-na夫e patients and in 78% of PI-experienced patients at 36 weeks. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-20. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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The emerging data on ABT-378 remains impressive. Most clinical investigators working with the drug believe it to be well-tolerated. The success of this drug likely reflects a critical pharmacologic issue: viral suppression is partially dependent on drug exposure. Exposure is determined by adherence and drug metabolism (both factors favouring ABT-378 over other protease inhibitors). Unfortunately the "salvage" part of this study enrolled patients who had failed only one protease inhibitor who were na夫e to NNRI's. These patients were still frequently sensitive to currently available PI's. No control arm (such as ritonavir/indinavir) makes the results very difficult to interpret. The contribution of ABT-378 in this situation cannot be interpreted and whether it is any better than response to a second-line double PI combination remains unknown. |
Steven G Deeks, MD. HIV InSite.
Tenofovir disoproxil, also known as bisPOC PMPA, is an oral nucleotide analogue in development at Gilead Pharmaceuticals.
Schooley and colleagues randomised 189 patients (median baseline HIV RNA of approximately 3.75 log10 and on stable antiretroviral therapy for at least 8 weeks) to receive 75, 150, or 300 mg of tenofovir once daily versus placebo. At week 24, the median decline in HIV RNA was 0.29, 0.33, and 0.83 log10 for the 75, 150, and 300 mg arms, respectively. The placebo group experienced a median HIV RNA increase of 0.28 log10. All patients on the placebo arm were rolled over to the 300 mg arm after 24 weeks. Of the patients on active treatment, 4.4% discontinued therapy versus 7.4% of the patients on placebo. Despite significant reductions in viral load, there was no CD4+ T cell rise. Serious adverse events were infrequent, and no evidence of nephrotoxicity was observed.
Ref: Schooley R et al. A double-blind, placebo-controlled study of tenofovir disoproxil fumarate (TDF) for the treatment of HIV infection. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-19. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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Tenofovir is a well-tolerated drug that has clear activity against resistant viruses. Patients in this study likely had ongoing partial viral suppression from their regimen. Achieving an additional 0.83 log10 decline is impressive. More importantly, the lack of nephrotoxicity in these closed monitored patients suggests that this drug should prove to be safer than adefovir dipivoxil. The lack of any observed CD4+ T cell benefit among patients in this tenofovir study could be of concern. Data are certainly more encouraging than the more advanced PMEA and should spur Gilead to more rapidly with PMPA. |
Steven G Deeks, MD. HIV InSite.
T-20 is a peptide therapeutic that inhibits the ability of HIV to attach to the CD4+ T cell receptor, thereby inhibiting fusion between the virus and the cell membrane. It is the first "fusion inhibitor" to be developed and represents the most promising advance in the past year for heavily pre-treated patients.
In a non-controlled, single arm study, 71 patients enrolled on prior T-20 studies received open label T-20 (50 mg twice daily) for 16 weeks. Along with T-20, patients were encouraged to initiate the best antiretroviral agent available (using genotypic testing).
Patients were heavily pre-treated: 93% of patient had received drugs from 3 classes in the past (nucleoside analogues, non-nucleoside reverse transcriptase inhibitors and protease inhibitors). The median number of prior antiretroviral drugs was 11. The median baseline HIV RNA was 4.9 log10 (approximately 80,000). Baseline genotypic analysis revealed a median of 13 mutations associated with resistance to currently available agents.
Data were presented on the first 64 patients to reach week 16 of follow-up. Using an intent-to-treat analysis, 53% of patients had an undetectable HIV RNA level (< 400 copies/mL) or had a greater than one log decrease in HIV RNA from baseline. T-20 in this very advanced patient population appeared to be well-tolerated. Other than local injection site reactions (all mild), there were no clear drug-related complications. The vast majority of patients were able to remain adherent to twice-daily subcutaneous injections.
Ref: Lalezari, J et al. Sixteen week analysis of heavily pre-treated patients receiving T-20 as a component of multi-drug salvage therapy. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract LB-18. Report source: HIV InSite, UCSF Positive Health Program. See: http://hivinsite.ucsf.edu
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T-20 is clearly a potent anti-HIV agent. It should prove to be very effective for treatment experienced patients. However, due to the uncontrolled nature of this study, it is very difficult to determine what role T-20 had in causing viral suppression. The patient population was heterogeneous. A significant number of patients had a brief holiday before restarting therapy (this may result in an improved 16-week response to therapy). Some patients received a "mega-HAART" type regimen. Recognising the limitations of the efficacy data, the safety and tolerability data remains very impressive. The vast majority of these very advanced patients were able to take a twice-daily subcutaneous injection for up to 16 weeks. Due to limited options for patients with three-class virologic failure, there will be immense pressure on Trimeris and Hoffmann-La Roche to develop T-20. Several concerns remain, including: (1) the optimal dose has not been defined, (2) drug supply remains limited, (3) there are theoretical concerns that T-20 will generate neutralising antibodies, (4) resistance to T-20 may be inevitable for patients unless of effective agents can be used concurrently and (5) it remains unclear whether patients can take twice-daily injections indefinitely. |
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MISCELLANEOUS
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Deirdre Maclean, senior writer, CATIE
The most common and probably most annoying side effect of nelfinavir is diarrhoea. In a small study involving 24 patients, calcium supplements reduced nelfinavir-induced diarrhoea in as little as 48 hours.
Before taking part in this study, 50 per cent of the patients reported their diarrhoea as mild (grade 1, one to three loose stools per day), 42 per cent described it as moderate (grade 2, three to seven loose stools per day), and eight per cent rated it as severe (grade 3, more than seven loose stools per day). All patients had been taking at least one anti-diarrhoea drug.
The subjects were given 500 mg of calcium twice a day and were asked to report any changes in bowel activity after a minimum of 48 hours. All 24 patients reported improvement, with 16 ( 67 per cent) reporting normal stools and eight (33 per cent) mild diarrhoea.
These results suggest that calcium tablets, which are relatively cheap and non-toxic, may be a useful way to relieve nelfinavir-induced diarrhoea.
Ref: Perez-Rodriguez E et al. The role of calcium supplements in the treatment of nelfinavir-induced diarrhoea. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1308. Source: Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Paul Blanchard, ATP.
Psyllium husk is a plant fibre derived from the seeds of Plantago species. It is used both for diarrhoea as a bulking agent, improving faecal mass and consistency, and it may also help constipation by softening faeces and promoting peristalsis. Psyllium husk is also known as ispaghula in the UK.
The first report of using psyllium for nelfinavir related diarrhoea was by T Hawkins at the 1998 International Conference on AIDS. A telephone survey of patients at a New Mexico practice on nelfinavir established that 26% used psyllium husk, usually once daily, to control diarrhoea. T Ronagh and colleagues at a Las Vegas practice reported at ICAAC on the use of psyllium husk fibre bars, which may be preferable to psyllium powder which has taste and convenience problems.
16 patients with a history of persistent diarrhoea associated with PI use were asked to consume 2 psyllium husk fibre bars before bed for a two week period. Efficacy, taste and adherence was assessed by pre and post study self-completed survey. Prior to the use of the fibre bars diarrhoea was reported as grade 1 (mild) by 29%, grade 2 (moderate) by 64% and grade 3 (severe) by 7%. After 2 weeks of fibre bar consumption the mean grade of diarrhoea improved from 1.75 to 0.93, with 50% reporting normal stools. All patients reported liking the taste and found the bars easy to adhere to.
In conclusion, 93% of the study participants reported that the psyllium husk fibre bars improved their diarrhoea symptoms and were convenient to take. The low cost of this intervention was also highlighted (five US dollars for 2 weeks).
Ref: Ronagh T, Schoeder D. Psyllium husk fiber bars are efficacious in the treatment of protease inhibitor (PI) induced diarrhea. 39th ICAAC; September 26-29, 1999; San Francisco, CA. Abstract 1307.
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Psyllium husk is available as a powder or in sachets both over the counter and by prescription in the UK as the brands Fybogel, Fybozest, Isogel, Konsyl and Regulan. Fybozest is also approved as a soluble fibre for reducing elevated levels of cholesterol. Psyllium husk containing snack bars may be available through health food shops but ATP has so far failed to identify a supplier in the UK. |
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OTHER NEWS
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U.S. Bioscience has announced that the company has suspended clinical testing of lodenosine (FddA) and that its IND is on clinical hold pending review of additional scientific information regarding serious adverse events seen during a Phase II clinical trial, including a recent patient death.
The Phase II trial was designed to evaluate the efficacy and safety of three different dosages of lodenosine, a nucleoside reverse transcriptase inhibitor, in combination with two additional antiretrovirals for the treatment of HIV-infected adults, compared with a control group. The trial enrolled approximately 176 patients on lodenosine at 27 clinical centres in three countries. Effective immediately, all patients are being discontinued from lodenosine and are being monitored closely.
Source: Company press release.
Prophylactic treatment with nucleoside analogues during the perinatal period to prevent vertical HIV transmission appears to increase the risk of mitochondrial dysfunction in children, according to a French team of investigators.
In the September 25th issue of the Lancet, Dr. Stephane Blanche of Hopital Necker Enfants Malades in Paris and colleagues describe eight children who developed persistent mitochondrial dysfunction following perinatal exposure to zidovudine or zidovudine plus lamivudine.
Dr. Blanche's group identified the eight children, who were unrelated and not infected with HIV-1, from the French National Epidemiological Network for mother-to-child transmission of HIV-1. Five children presented with delayed neurological symptoms, and two of these five children died. The other three children were without symptoms, "...but had severe biological or neurological abnormalities."
"All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment," the investigators write. "No mutation currently associated with constitutional disease was detected in any patient."
Based on these findings, Dr. Blanche's group suggests that there may be a "...link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues." Nonetheless, until more data are available, they believe that current recommendations for prophylactic zidovudine to prevent vertical HIV-1 should be maintained. However, "[p]regnant women should be informed of the potential side effects associated with these treatments during pregnancy."
If the findings reported by Blanche et al. are confirmed, "...perinatal NRTI [nucleoside analogue reverse transcriptase inhibitor] therapy could be associated with 0.1% mortality and 0.4% morbidity," according to two editorialists. Drs. Andrew A. M. Morris of the Royal Victoria Infirmary in Newcastle-upon-Tyne, UK and Andrew Carr of St. Vincent's Hospital in Sydney, Australia also point out that the potential benefits of treatment outweigh these risks.
They add that the development of less toxic agents is needed. In the meantime, they suggest that "...non-NRTI drugs such as nevirapine may prove safer and equally effective in reducing the rate of perinatal HIV transmission."
Ref: Lancet 1999;354:1046-1047,1084-1089. Source: Reuters Health
Researchers from the University of California at San Diego conducted a retrospective analysis of 141 patients and found that three were infected with HIV with a more than tenfold resistance to one or more AIDS drugs. More than one-quarter of the patients showed a reduced susceptibility of greater than 2.5 to 10 times to at least one drug. The patients, who were enrolled from 1989 to 1998, were located in San Diego, Los Angeles, Dallas, Denver, and Boston. The researchers suggest that resistance testing may be indicated to assess the frequency of drug resistance over time and to determine the potential for geographic variability. They also note that "the cost-effectiveness of resistance testing should be evaluated in the context of efforts to rapidly identify and optimally treat those patients infected with drug-resistant virus."
Ref: Little SJ et al. Journal of the American Medical Association (22/09/99) Vol. 282, No. 12, P. 1142. Source: CDC HIV/STD/TB Prevention News Update
HIV-1 Drug Resistance in Newly Infected Individuals
Researchers report that they found a 16.3 percent prevalence of HIV-1 variants with known resistance-conferring genotypes to any antiretroviral drug in a group of newly infected patients from New York and Los Angeles. Of the 67 patients for whom resistance could be tested, approximately 27 percent were at least threefold resistant to at least one antiretroviral drug. Three of those patients were diagnosed with multidrug resistance. The researchers, led by Daniel Boden of the Aaron Diamond AIDS Research Center, assert that their findings reinforce the need for increased use of resistance testing in the setting of primary HIV-1 infection. Because the study group may not be indicative of new HIV-1 cases in general, the researchers recommend additional research to examine both the genotype and phenotype of transmitted viruses.
Ref: Boden D et al. Journal of the American Medical Association. (22/09/99) Vol. 282, No. 12, P. 1135. Source: CDC HIV/STD/TB Prevention News Update