Novel strategies with existing drugs

14 September 2005. Related: Conference reports, Antiretrovirals, IAS 3rd Rio de Janeiro 2005.

Mike Youle MD Royal Free Hospital

This report focuses mainly on strategies for using existing drugs in difficult situations.

If 4,000 delegates were registered for this conference then I never saw more than 1,000 at any time and some of the sessions were sparsely attended. Part of this was due to the location as Rio is not an easy place to get to, especially from Africa and Asia. The Conference centre was an additional hour from town.

Almost every presentation showed extremely good response rates (which showed that we have the tools) and that mental health and substance abuse issues along with general adherence and poor medical care are high on the reasons for poor outcomes. We have a drug pipeline which is still exciting, but that we providers and the health care industry are fighting against cost and political problems that produce restrictions on how best we can deliver this effective treatment.

This was summed up in the slide presentation of Julio Montaner prior to the late breakers when he showed that experienced medical care is as great a factor in the success of treatment as the drugs themselves. [Wood et al, CROI 2002].

This report looks at the following treatment strategies:

Reduced PI combination of indinavir/ritonavir 400/100
5 days on HAART, 2 days off
Kaletra monotherapy

Reduced PI combination of indinavir/ritonavir 400/100 in Mali

The trend to use simple regimens for the developing World, driven mainly by cost, leaves many people nervous that there is a tsunami of resistance building up that will require more complex and costly intervention.

That is not to decry the efforts to treat the millions who need it in resource-limited nations but it was comforting to see at least some attempts to use PI based HAART first line with good outcomes using indinavir 400mg/ritonavir 100mg in the NOGOMA study in Bamako, Mali. [1] This study is supported by Solthis (www.solthis.org), spearheaded by Christine Katlama and her team.

Thirty patients were switched from indinavir (IDV) 800mg TID to 400/100 BID and the problem of refrigeration of ritonavir was overcome by the use of thermos flasks or by the use of unglazed earthenware pots soaked in water (the contents are cooled by the latent heat of evaporation). The results of this boosted PI regimen were as good as in any other studies with 96% having adequate IDV Cmin levels, 93% <400 copies/mL and no PI mutations seen in the two subjects who had detectable viral load.

5 days on HAART, 2 days off

Continuing the theme of less is more the mellifluous Cal Cohen, showed 48 week data of the FOTO study where he adapted the regimen of 30 subjects (10 on efavirenz (EFV), 10 on nevirapine (NVP) and 10 on protease inhibitor (PI) based regimens, all with at least two nucleosides (NRTIs) in their regimen) to take therapy only during the 5 weekdays and to miss the weekend doses. [2]

This pilot study showed that 100% of the EFV based patients maintained suppression and 90% of the NVP based patients (the one subject was lost to follow-up after a blip to 511copies/mL. Two of the patients using PI-based combinations had rebound but re-suppressed on daily dosing, this may be reflected by the serum levels, which were below adequate trough levels for PIs after 2 days off drug. The dosing schedule was much preferred by the patients and was well tolerated and reduced cost by 28%.

Kaletra monotherapy

Jose Arribas had two posters following up on his Only Kaletra (OK) study which assessed what happened if the NRTI backbone was stopped in 21 of 42 subjects. [3]

Patients who simplified had been <50 copies/mL for a median of 28 months. CD4 count before the switch was 662 cells/mm³, nadir CD4 was 139 cells/mm³, and viral load previously was 100,000 c/ml before HAART. Patients who remained on triple-HAART had been <50 copies/mL for 15 months, CD4 was 585 cells/mm³, nadir CD4 was 90 cells/mm³, and viral load previous to HAART was 100,000 copies/mL.

At week 48, 81% on Kaletra monotherapy and 95% on triple-HAART had <50 copies/mL (ITT, MD=F). In the triple-HAART one patient discontinued due to hyperlipidaemia. On Kaletra simplification three patients lost viral suppression and one was lost to follow-up. Viral suppression was defined as two viral loads >500 copies/mL, two weeks apart. All three patients with loss of viral suppression added nukes (either AZT/3TC or d4T/3TC) and re-suppressed viral load <50 copies/mL. Preliminary data show that failure of these three patients was not associated with the development of primary resistance mutations. One patient had no genotypic mutations; the second patient developed L63P & V77I; the third patient developed V77I. There appeared to be an association with losing virologic control and poor adherence as measured by the validated GEEMA adherence questionnaire.

JE McKinnon reported for his research group, which included John Mellors, on levels of persistent viraemia after simplification in the OK study [4] using a Roche assay with a limit of 3 copies/mL. For patients who remained <50 copies/ml the levels of virus using the sensitive assay were the same, median 3-6 copies/mL, throughout the 48 weeks. So patients who simplified to Kaletra monotherapy and maintained <50 copies/mL did not have different levels of persistent viraemia when using this sensitive assay. Patients on Kaletra monotherapy had the same percent of undetectable viraemia (30%) as patients remaining on triple-HAART through 48 weeks.

However, when comparing patients on Kaletra monotherapy who lost viral suppression to those who did not: at baseline there was no difference in median viral load, but at week 8 median viral load was higher (not significant) among the 4 failure patients compared to the patients who remained suppressed. At week 12 the difference in median viral load between failures and non-failures appeared a little wider, and by week 24 the failures (n=3) had a statistically significant higher median viral load (about 3 logs) compared to patients who retained viral suppression. This suggests that at least for a few patients monotherapy may not be ideal and it appears this may be for those in whom adherence is an issue.

This article has been edited from a report posted to the NATAP.org website that will also appear in the next edition of the Journal of Viral Entry.

References:

All references are to the Abstracts from the 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janiero, July 2005.

Cisse M, Canestri A, Marcelin A-G et al. A boosted protease inhibitors (PIs) strategy with ritonavir (RTV) 100 mg /indinavir (IDV) 400 mg in HIV-1 infected patients in Mali (Bamako): the NOGOMA Study. Abstract MoPe11.7C08.
Cohen C, Colson A, Morris A et al. The FOTO study 48 week results: viral suppression can be maintained when antiretrovirals are taken five consecutive days on, and two days off each week. Abstract WePe12.4C10.
Arribas JR, Pulido F, Delgado R et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression. A randomized, controlled, open label, pilot, clinical trial (OK Study): 48 weeks analysis. Abstract WePe12.3C05.
McKinnon JE, Arribas JR, Pulido F et al. The level of persistent viremia does not increase after simplification of maintenance antiretroviral therapy to lopinavir/ritonavir alone. Abstract WeOa0203.