Report 2 -  4th International Workshop on HIV Drug Resistance and Treatment Strategies
Written by Jules Levin
Sitges, Spain, June 12-16 2000

Brief Overview of Selected Highlights from the Resistance Workshop 4th International Workshop on HIV Drug Resistance & Treatment Strategies

  Today was the first sunny beautiful day in Sitges, Spain since I arrived several days ago. So I went for a swim in the Mediterranean and the pool, and a jog. As a result I'm too tuckered out to write much. By the way it's a delicious night--cool and balmy with just the right breeze. This will be a brief report outlining key information presented at this meeting. More detailed reports will follow. Just a little something to update you on the discussions here. Look for more extensive coverage soon.  

New Antiretovirals - (previously sent)

Resistance Testing

In the ABT-378 report emailed yesterday I related the concerns expressed here regarding resistance testing: there is some discordance between genotypic and phenotypic tests, interpreting and applying the results of assays are more complicated than one may think, misuse of the results can be harmful to patients, the differences in phenotypic cut-offs between the Virco Antivirogram (<4-fold is the low-level cut-off)) and the Virologic PhotoSense (<2.5 fold is the low level cut-off) tests can create confusion, cut-offs may be different for different drugs but assays currently use standard cut-offs, new mutations are discovered over time. Researchers discussed these concerns a great deal. I think that over time these concerns will be addressed but until then care must be exercised in using resistance test results.

Most experts generally believe, although there are some dissenters, that resistance testing is a helpful tool for making treatment decisions. Several key studies have supported that--Viradapt, VIRA3001, GART. But these studies all have flaws. The preliminary results of two studies, also considered very flawed, were presented here (NARVAL and HAVANA) which did not show clear benefit to resistance testing over making decisions without resistance testing. Researchers at this meeting generally found a number of reasons to reject these two studies.

There was a good deal of discussion about how pharmacology and drug blood levels inside cells and outside cells may affect treatment success or failure. It was agreed this area needs much attention but has not received much yet.

Intermittent Viral Load Blips

At the Retrovirus Conference an abstract described the occurrence of intermittent viral load "blips". Two studies presented at this meeting reported that intermittent blips (>50 copies/ml) occur in people with plasma viral load <50 copies/ml. One study (Merck 035) found that 0/6 people who experienced such blips did not experience viral load rebound in 5 years follow-up. In another ACTG study (343) 40% (96/241) experienced intermittent blips but were not viral rebounders (2 consecutive HIV RNAs >200 copies/ml) after an average follow-up of 84 weeks. However, in several discussions I had with researchers in the hallways they expressed concern that given more time (>3-5 years) viral rebound might occur. One suggestion is to intensify treatment if blips occur. Another study found resistance developed during these blips although individuals were able to return to undetectable viral load and maintain it for an average follow-up of 12 months. The author of this paper also said in conversation with me that she felt eventually viral rebound would occur.

Resistance, Reservoirs, and Therapy Interruptions

Two studies discussed their findings of virus in reservoirs despite undetectable HIV RNA in plasma. One study reported on 56 patients receiving d4T/3TC/NFV/SQV HGC with or without IL-2 after >6 months of undetectable plasma viral load (ultrasensitive PCR). 21/31 patients had detectable virus in lymph nodes, while 10 had undetectable virus in lymph nodes. There was no difference between those with or without IL-2. The author reported it as residual virus replication but someone in audience questioned whether it was expression of virus or replication. Residual virus was associated with lower trough levels of saquinavir & nelfinavir, but not with baseline viral load, time to undetectable plasma virus, or pretreatment proviral DNA. HIV RNA was negative in the CSF of the 10 who had undetectable virus in plasma.

In a second study the authors reported that intracellular HIV RNA in PBMC could persist in the absence of detectable plasma HIV RNA. The author reported to me that he observed viral decay in this reservoir when individuals were treated during acute infection but not when treated during chronic infection.

One study reported that small minorities of resistant virus persist in patients undergoing STIs (therapy interruptions) following HAART failure when conventional genotyping detect no resistance in plasma. He said these resistant populations may be critical in the response to the reintroduction of HAART after the interruption.

Indinavir/ritonavir (800/100)

In a study of 800 indinavir and 100 ritonavir twice a day, renal toxicity was observed in 33% of 59 patients. Drug discontinuation was necessary in 6 (10%), and in 7 patients RTV/IDV dose was adjusted to 400/400. Indinavir trough levels were reported well above IC95 (median 1.75 mg/l, IQR 1.07-2.57), but ritonavir trough levels were below the IC95 in 88% of patients. At month 3, patients with IDV levels above the median (>7.09 mg/l) had a mean viral load decrease of 2.86 log in comparison with 0.66 log in those below the median IDV peak level (P=0.04), and at month 6 the decrease was 1.75 versus 0.5 log. After 24 weeks, the median decrease in viral load in patients exhibiting or not exhibiting Val82Ala and Leu90Met mutations were 1.33 log and 1.85 log, respectively. A close correlation was observed between higher peak levels of indinavir and nephrotoxicity.

Are Low Level Reductions NNRTI Susceptibility Due to Transmitted Resistance Or Not?

Over the course of the past year including at last year's Resistance Workshop concerns were raised about the reported high incidence of low level NNRTI resistance. This year several researchers reported that their findings suggest these low levels (4-10 fold) of resistance are not due to NNRTI transmitted resistance but likely are due to the evolution of primary drug resistance or polymorphisms (natural resistance mutations which can occur with protease inhibitors as well). Lee Bacheler of Dupont reported that despite these low levels the efficacy of efavirenz combination therapy in NNRTI-naÔve subjects did not appear to be negatively affected by pre-existing low level phenotypic resistance to NNRTIs. Most subjects (5/6) with high level phenotypic resistance to one or more NNRTIs subsequently failed efavirenz combination therapy. Although it appeared as though a number of researchers think these low levels of resistance will respond well to NNRTI therapy, a number of researchers said this should be studied further and some are not yet convinced that the low level resistance is not a concern. 

Resistance Prevalence

Quest Labs and Stanford University reported from a database (11,000 samples) they collected that over a 24 month period there has been a significant increase in multidrug resistance in patient samples submitted for testing to a clinical lab. Significant increases were observed in the fraction of samples resistant for the NNRTIs nevirapine (S1 '98: 22.2%; Q4 '99 43%), delavirdine (S1 '98: 19.8%; Q4 '99 39%), and efavirenz (S1 '98: 18%; Q4 '99: 38%). The frequency of the K103N mutation associated with NNRTI resistance has more than doubled, accounting for NNRTI resistance. Lesser increases were seen in NRTI and PI resistances. The authors concluded that the development of new drugs designed specifically to target the most common resistant variants of HIV-1 RT and protease may prove to be a more effective strategy for combating the spread of resistant virus.

Resistance In Newly Infected

Virologic and Aaron Diamond AIDS Research Center reported on their monitoring of the incidence of drug resistance in among newly infected individuals. They assessed baseline resistance in all 41 newly infecteds referred to the ADARC during April 1 1999 to March 31 2000. Three patients were identified with significant phenotypic resistance to any drug, including two cases of multi-drug resistance. MDR virus number 1 revealed a highly reduced susceptibility to all protease inhibitors beside amprenavir as well as 49-fold reduced susceptibility to AZT (genotype- RT M41L, D67N/S, T69D, V118I, T215Y; protease- K20I, M36I, M46I, L90M); number 2 virus: >50 fold reduced susceptibility to all 3 NNRTIs and an intermediate 6-fiold resistance to NFV (genotype: RT K103N, Y181C; protease: K20I, M36I, L90M; number 3 virus: high resistance to NVP (10.9-fold) and DLV (33.6 fold) was detected. The overall prevalence of any resistance conferring codon changes in RT was 27% (10/36). Substitutions frequently involved in protease gene polymorphisms were  L63P/Q/C/S (53%), V77I (28%), L10F/I (13%), I93L (25%), and M36I (15%). L90M was the only primary mutation detected in protease (5%). Hypersensitivity to any NNRTI (<0.5 fold) was seen in 6 individuals, of whom only two showed classical AZT mutations. The authors concluded that in comparison to previous years they documented increasing prevalence of genotypic altered viruses. Clincal relevance has yet to be established.

TO BE CONTINUED. Tomorrow's sessions are a half-day and that ends the conference.