Antiretrovirals and other stuff!

Mike Youle and Jules Levin for

Cold fair Dublin in the far West of Europe had its best face on for this 10th European AIDS Clinical Society Conference, the sun shone and the conference attracted a large number of delegates from across the entire sub-continent. The quality of the presentations was high and the meeting continued to be a cross between education and the showing of new data for both treatment and care. So here is a selection of new agents presented at the meeting.

CCR5 inhibitors

This was a stormy month for the CCR5 inhibitors with both vicriviroc from Schering-Plough and aplaviroc from GlaxoSmithKline (GSK) running into trouble. The last of the three agents in clinical trials with a clean sheet is maraviroc developed by Pfizer, although a single case of severe liver toxicity has been reported, it appears that this is much more likely to be related to concomitant medication with known liver-toxicity.

Of the two presentations on the drug at the EACS meeting the first was of in vitro interaction data between maraviroc (formerly UK427,857) and 17 other approved antiretrovirals, including enfurvitide. [1]

Additive interactions were seen with most drugs (14/17) with synergy noted for atazanavir, indinavir and enfurvitide, but on further testing, an additive effect was seen there also; importantly no antagonism was found. The second study confirmed that although some postural hypotension (drop in blood pressure on standing) was reported in the early studies this agent does not have a significant effect on cardiovascular function [2]

Integrase inhibitor: MK-0518

Probably the most exciting presentation of the whole meeting was that given by Javier Morales-Ramirez on the integrase inhibitor from Merck; MK0518 [3].

MK-0518 is an agent that prevents HIV from incorporating its genetic information into that of the host cell, thereby preventing established infection of CD4 cells. It has shown good efficacy in vitro and is synergistic with many available HIV drugs. Since it has a novel mode of action, within the nucleus of the cell, there should be no cross-resistance. Thus, it represents a new option for those with multi-drug resistance. The good news continued with no safety issues from early studies and good tolerability and no requirement to dose with food.

In this randomised, double-blind, placebo-controlled study twenty eight treatment-naive patients received 10 days of monotherapy with MK-0518 (at doses of 100mg, 200mg, 400mg or 600mg) and seven study participants received placebo. HIV viral load reductions were a potent -1.7 to -2.2 log for the various doses of the integrase inhibitor administered. 50-57% of patients receiving MK-0518 achieved <400 copies/mL and 13-29% achieved <50 copies/mL viral load. The drug appeared safe and well tolerated with no serious adverse events and no discontinuations due to adverse events.

Mean baseline HIV RNA across the groups was 4.53 to 4.97log and mean baseline CD4 count was 256-569 cells/mm3. No drug related adverse events were seen with any consistency. At day 10, viral load reductions ranged from -1.7 to -2.2 log for individuals receiving MK-0518.

Overall these are very encouraging results and a Phase II dose-ranging study is underway against efavirenz. Watch this space!

Protease inhibitors: GW640385 (brecanavir), tipranavir, Kaletra monotherapy, saquinavir 500mg

GW640385 is a novel aspartyl protease inhibitor (PI) being developed by GSK and about to enter Phase 2 trials. An in vitro study against a panel of multiple resistant isolates (containing mutations at positions 32, 33, 46, 47, 50, 54, 82, 84 and 90) was presented by Yates and showed that compared to the current PIs, TMC114 and tipranavir were not included, this agent showed good effect when cultured with these isolates [4]. Only two virus showed >5 fold resistance to this drug and 11 with >2.5 fold changes. GW640385 was consistently the most potent of the PI’s tested but no signature mutation or pattern emerged in this study. We will look to clinical studies for more information about how this drug will perform. [See report later in this issue of HTB for virological data on brecanavir that was presented at ICAAC].

A number of new presentations on tipranavir/r (TPV/r) were shown, consisting mainly of follow-up of the large RESIST studies, which randomised three-class experienced patients to optimized background regimen (OBR) plus either tipranavir/r or comparitor PI/r.

That of Cassetti from Buenos Aires focused on those who in the two large studies had reached the treatment response of > 1log reduction in viral load at week 24 (240/582 [41.2%] and mapped what happened to them [5]. Of these 79.6% reached <400 copies/mL and 55.8% (134/240) achieved <50 copies/mL and the median viral load drop was 2.6log, with 75% getting at least 1.8log reduction. Median CD4 cell rise was 88 cells/mm3 in responders compared to 11 in non-responders. Moreno showed further data on the use of genotypic sensitivity score (GSS) in the RESIST studies using the Virtual Phenotype or Trugene assays [6].

These showed that the percentage responding to tipranavir increased as the GSS score became greater. One of the problems with this analysis is that the exact link between particular combinations of mutations and resistance to tipranavir remains somewhat uncertain making this, at best, a guide to the likelihood of success with the drug.

Another cut of the RESIST data surfaced in a poster by Charles Farthing, which stratified outcome by viral load and CD4 response, [7] suggesting that neither of these parameters predicted a poor outcome, and that all subgroups did better with tipranavir as a new PI.

  • TPV/r provided superior efficacy to CPI/r regardless of baseline viral load and CD4 cell count
  • TPV/r improved virologic response even in patients with high baseline viral loads (>100,000 copies/mL)
  • Patients in the TPV/r arm with low baseline CD4 cell counts (<50 cells/mm3) had an improved treatment response compared with those in the CPI/r arm
  • In treatment-experienced patients, TPV/r provides a good treatment response in patients with both high and low viral loads.

For patients with <10,000 copies/mL at baseline, 56% had treatment response with TPV/r vs 31% for CPI/r; 41.7% of patients with viral load of 10,000 to 100,000 copies/mL who took TPV/r achieved a treatment response compared to 19% taking CPI/r; and for patients with >100,000 copies/mL at baseline 35% taking TPV/r vs 13.7% taking CPI/r achieved a “treatment response”.

Response to TPV/r was the same regardless of whether baseline CD4 count was >350, 200-350, or 50-200 cells/mm3 (see Table 1). When CD4 count at baseline was <50 cells/mm3, the treatment response was less for patients taking TPV/r, but it was still superior to patients who received CPI/r (26% vs 9%).

Table 1: Percentage of patients with treatment response stratified by baseline viral load and CD4+ cell count

Baseline value Tipranavir/r Comparator PI/r
VL <10,000 56.0 * 31.1
VL 10-100,000 41.7 ** 19.4
VL >100,000 34.9 * 13.3
CD4 >350 46.0 *** 21.2
CD4 201-350 44.4 * 23.0
CD4 51-200 46.5 * 21.23
VL <50 26.3 **** 9.5

*p<0.0001, **p=0.0009, *** p=0.0002, **** p=0.0016

Yet more slicing, produced the outcome reported by Jurgen Rockstroh, that when stratified by previous PI use, no diminution of “treatment response” in the 24-week outcomes was seen when tipranavir was introduced [8]. When evaluating <400 copies/ml response by reduction in viral load, previous PI did appear to matter.

Table 2: Percentage of patients with treatment response <400 copies/mL stratified by previous PI use

No. previous PIs Tipranavir/r Comparator PI/r
2 47.1 38.5
3 47.1 32.1
4 39.3 16.1
5 40.4 13.9
6 38.0 3.7
  • The overall treatment response (=1 log reduction in two consecutive viral load measurements) for patients in the TPV/r arm was 41.2% (240/582) vs 21.3% (109/577) in the CPI/r arm
  • Patients in the TPV/r arm had a consistently improved treatment response compared to the CPI/r arm in all PI strata
  • Almost 50% of TPV/r patients with three or fewer previous PIs achieved a treatment response
  • The difference in treatment response became more dramatic as the PI experience of patients increased
  • In those with six previous PIs, TPV/r had a 10 times greater treatment response than in CPI/r patients (38.0% [35/92] for TPV/r vs 3.7% [3/81] for CPI/r)
  • Approximately 40% of TPV/r patients presenting with 4 to 6 previous PIs at baseline achieved a treatment response

Table 3: Percentage of patients with virologic response at 24 weeks stratified by previous PI use

<400 copies/mL <500 copies/mL
No. previous PIs TPV/r CPI/r TPV/r CPI/r
2 43.1 38.5 25.5 25.0
3 44.2 27.4 32.7 17.0
4 35.5 9.1 25.8 6.3
5 29.2 9.2 19.9 5.2
6 23.9 3.7 17.4 2.5

Table 4: Viral load change at 24 weeks stratified by previous PI use

No. previous PIs TPV/r CPI/r
2 -1.25 -0.84
3 -1.51 -0.44
4 -0.59 -0.20
5 0.91 -0.24
6 -0.87 -0.11

In addition data that showed some increase in liver-related laboratory abnormalities in patients who were co-infected with HBV (3.5% of the study population) or HCV (6.6%) was shown by Stefan Mauss [9]. How this will translate into clinical practice and to what degree it is due to the higher doses of ritonavir used compared to other PIs will require information from the ongoing studies of tipranavir/ritonavir (500/100mg bid).

After all these posters the meatiest data came in an oral presentation by Pedro Cahn, who showed a 48 week meta-analysis of the RESIST 1 and 2 studies [10]. At last some data separated out the effect of enfurvitide (T-20) from tipranavir within the study although Boehringer-Ingelheim seem still coy about showing the data of tipranavir versus tipranavir plus T20 for fear of isolating their agent to the salvage situation, a view seemingly held by marketers rather than scientists. The subgroup who received both drugs as new agents did much better. Since tipranavir is limited in terms of which antiretrovirals it can be dosed with, and although data now exists showing no significant pharmacokinetic interaction with maraviroc [11], it would seem a wise course of action to use as many active drugs together as possible, rather than risk burning through each agent as mono- or sub-optimal therapy.

Although reasonably well tolerated there were greater AST/ALT and triglyceride changes in the tipranavir arms and it remains to be seen if the reduction of ritonavir to 100mg twice-daily in the naive studies will translate into fewer abnormal values.

Clinical data on TMC114 (the new PI from Tibotec), was provided by Montaner and colleagues. They reanalysed the POWER studies, to evaluate the potential clinical and mortality endpoints, using the CD4 and viral load data from week 24. They used two methods of either regression, using a meta-analysis of randomised clinical endpoint studies conducted before the introduction of HAART, or categorisation, using data sets derived from cohort studies of CD4 and clinical progression rates in HAART treated patients [12]. The additional effect of TMC114/r, over the comparator PI/r, in raising CD4 levels and suppressing VL, were predicted to lower progression rates to AIDS or death by 48% using the categorisation method, and 55% with the alternative regression analysis. The use of these analyses has become evermore helpful since it is no longer ethical or practical to conduct large-scale clinical endpoint studies in late stage HIV disease.

Jose Arribas showed an updated set of information on the OK study in which he evaluated lopinavir/r (Kaletra) as monotherapy in patients who had never failed a PI and were suppressed to <50 copies/mL for more than six months [13]. After 72 weeks the percentage of individuals at VL <50 (ITT-M=F) was 81% in the monotherapy group and 90.5% in the continue HAART group (p=0.38). There were three transient blips in the monotherapy arm and two in the triple therapy arm. Four subjects had viral failures whilst on Kaletra which were re-suppressed by the re-addition of the nucleosides. A much larger study is ongoing in Spain that will more clearly define the risks and benefits to this approach. Finally a cost-effectiveness study has been performed within the OK study [14] which showed a cost-effectiveness ratio for Kaletra monotherapy of 5,186 Euros per unit of effect achieved (VL<50 at week 48) compared to 8,688 Euros for the standard triple therapy arm, suggesting that monotherapy could be more cost-effective as an intervention.

Tabatha Mahungu presented data on all HIV-infected patients attending the Royal Free Centre for HIV Medicine who had received SQV-500mg in a retrospective cohort study from September 2004 until October 2005 [15]. 137 adults were enrolled taking SQV-500-containing regimens that included SQV/r 1000/100 mg twice-daily (n = 116) or 2000/100 mg once-daily (n = 19). They were followed for a median of 275 (range 136–513) days.

Kaplan-Meier estimates showed that 95.6% (95% CI: 92.1, 99.0) of study subjects remained on SQV-500 therapy at 24 weeks and no new AIDS diagnoses or deaths were observed. Eighty four percent of the 92 subjects with <50copies/mL at baseline remained undetectable throughout whilst 15 subjects had one blip above this level during follow-up; no subject had sustained viraemia whilst taking therapy.

To assess the impact of SQV-500mg therapy on hepatic and lipid markers, measurements before and after initiation of SQV-500mg therapy were taken. No adverse changes in these parameters were noted.

The results of this 24-week retrospective cohort analysis provide an encouraging first insight into how SQV-500mg performs in clinical practice, with the majority of patients tolerating the formulation well and maintaining favourable virological and immunological responses.


Additional information on Interleukin-2 (IL-2) was provided from the GESIDA study from Spain. They assessed 162 patients who had at least one year on HAART, who either had a low level viraemia (<5,000 copies/mL), or who were undetectable (87%) [16]. Subjects had not had a CD4 rise >200 cells/mm3 and median CD4 at inclusion was 137. Median CD4 after a third cycle rose to 211 cells/mm3 (IQR123-289, p<0.0001) and 88.4% were undetectable. 44% had a CD4 increase to >200 cells/mm3, allowing discontinuation of prophylaxis for opportunistic infections. This study strengthens the data originally presented in the French ILSTIM study several years ago and suggests that this is a sensible and viable intervention for those with poor immune reconstitution. We still await the findings of the multinational SILCAAT study.

Adherence and personality

An interesting approach to the assessment of adherence was taken by Giola and co-workers in Varese, Italy. They evaluated 60 consecutive out-patients to evaluate, in a blinded fashion, if there was link between sub-optimal adherence and personality [17]. Previous work has suggested that health beliefs and interaction with health care providers is affected by personality. This however, is the first work in this area on HIV patients, as far as I am aware. Subjects filled in a validated personality test (Cattel’s 16PF) as well as a standardised questionnaire regarding their attitudes to HAART. The psychologist assessing the test was masked as to the therapy of the individuals. Twenty eight were on an NNRTI-based regimen and 32 on PI-based therapy. Eleven (34%) of the former group and 6 (21%) of the latter group were judged to be poorly adherent by the clinicians involved in their care. Underlying personality disorders such as low ego strength and poor compulsion control as well as depression and anxiety were strongly associated with poor adherence, with all 17 of the group who had been designated as poor adherers having one of more personality disorders, whilst the good adherers showed none of these traits (p<0.001). This study is important since whilst it is not possible to alter your underlying personality it is possible to modify the way people act within this framework.

Note: The reports in the article were selected from a longer review, which includes slides from the presentations. The full article can be read at


All references are to the Abstract Book of the 10th European AIDS Conference, 17-20 November, 2005, Dublin, Ireland.

  1. Mori J et al. The effect of maraviroc in combination with HIV reverse transcriptase inhibitors, NNRTIs, PIs and entry inhibitors against acute HIV-1 infection in vitro. Abstract PE7.1/2.
  2. Russell D et al. Investigation into the haemodynamic effects of oral mariviroc (UK-427,857) in healthy volunteers. Abstract LB 4.1/10.
  3. Morales-Ramirez JO et al. Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naive HIV-1-infected patients. Abstract LBPS1/6.
  4. Yates P et al. Genotypic and phenotypic analysis of GW640355: an assessment of the effects of specified resistance associated mutations alone or in combination with others in a survey of 50 viruses from PI-experienced patients. Abstract PE3.3/3.
  5. Cassetti I et al. Most tipranavir/r treatment responders achieve large viral load reductions, viral loads below dectedtion, and substantial CD4+ cell restoration. PE2.7/1.
  6. Moreno S et al. Impact of including genotypically sensitive antiretrovirals in a tipranavir boosted with ritonavir (TPV/r) regimen on viral load response. Abstract PE3.3/4.
  7. Farthing C et al. Superior efficacy of tipranavir boosted with ritonavir (TPV/r) vs comparitor boosted PI (CPI/r) in patients stratified by viral load (VL) and CD4+ count. Abstract PE7.3/22.
  8. Rockstroh J et al. 24-week analysis of the efficacy of tipranavir boosted with ritonavir (TPV/r) in HIV patients stratified by previous protease inhibitor (PI) use. Abstract PE7.9/11.
  9. Mauss S et al. RESIST 24-week efficacy and safety of tipranavir/ boosted with ritonavir (TPV/r) in hepatitis B (HBV) or hepatitis C (HCV) coinfected patients. Abstract PE13.3/4.
  10. Cahn P, Hicks C. RESIST-1 (R-1) and RESIST-2 (R-2) 48-week meta-analysis demonstrate superiority of protease inhibitor (PI) tipranavir+ritonavir (TPV/r) over an optimized comparitor PI (CPI/r) regimien in antiretroviral (ARV) experienced patients. Abstract LBPS3/8.
  11. Abel S et aql. Effect of boosted tipranavir on pharmaconkinetics of maraviroc (UK 427,857) in healthy volunteers. LBPE4.3/15.
  12. Montaner J et al. Prediction of clinical benefits of TMC-114/ritonavir from treatment effects on CD4 counts and HIV RNA. Abstract PE18.4/4.
  13. Pulido et al. Lopinavir/ritonavir as a single drug for maintenance of HIV-1 viral suppression. A randomised, controlled, open-label, pilot, clinical trial (OK Study): 72 week analysis. Abstract PE7.5/5.
  14. Escobar I et al. Pharmodynamic analysis of lopinavir/ritonavir monotherapy as maintenance therapy in HIV-1 infected patients. Abstract PE19.5/2.
  15. Mahungu T et al. Switching to saquinavir 500.r-based rtegimens in subjects on HAART is not associated with loss of virologic control. Abstract PE1.1/5.
  16. Lopez J et al. Interleulin-2 (IL-2) as treatment for immunological discordant patients with low CD4 cell counts after at least one year of HAART (GESIDA 33/03). Abstract PS3/1.
  17. Giola M et al. Adherence to antiretroviral therapy: underlying personality disorders can be more important than drugs’ convenience. Abstract PS3/2.

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