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Resistance Patterns
Reported by Jules Levin
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I just arrived in Barcelona for the international conference after a lousy flight on Iberia from Seville. I did not enjoy the food in Seville nor the hotel the meeting was at. Researchers attending the Resistance Wksp were very displeased with Iberia Airlines. A number of them had their luggage lost by Iberia on the way to Seville. And then on the flight from Seville to Barcelona Iberia removed all the luggage from the flight, and passengers had to weight for the next flight two hours later at the airport in Barcelona to get their bags. I felt the Resistance Wksp was a good meeting this year, particularly regarding new drugs in new classes (integrase & entry inhibitors) and in current classes. You can read NATAP reports from the conference at the NATAP website.
Genotypic Resistance Testing in Treatment Naive Patients
281 chronically HIV-infected treatment naive patients were enrolled in this study from 100 centers in the US. Mark Becker from Agouron reported the results of this poster in Seville. 44% were African-American, 26% Hispanic, 28% Caucasian, 79% male, average age 38. Baseline CD4 count was 200 and viral load 100,000. In patients reported to be treatment naive they found 8.9% (25/281) had evidence of resistance to antiretroviral therapy. 3.5% of patients had resistance to NRTIs, 5.3% to NNRTIs, and 0.7% to PI; 0.7% had resistance to 2 or more classes of HIV drugs. The authors suggested that performing baseline genotypic resistance testing in naive, chronically infected patients should be considered. Perhaps, the same should be considered for clinical studies in naive patients.
Phenotypic Testing May Underestimate Resistance in Newly Infected Individuals
Researchers from the CDC compared genotypic and phenotypic resistance test results from 79 blood samples. The patients had genotypic mutations associated with resistance to HIV drugs from a study of untreated newly diagnosed in 10 US cities, 1998-2000. Some patients analyzed for this study had new infection within 4-6 months, and some had chronic infection >6 months. 39% (n=31) of the blood samples with genotypic resistance had phenotypic resistance. Of the 19 newly infected individuals with genotypic mutations 14 (74%) had phenotypic resistance, and 29% (14) of the chronically infected with genotypic resistance.
Of the 19 blood samples from recently infected patients with genotypic resistance 14 had NRTI resistance, but 7 of the 14 had phenotypic NRTI resistance. Of the 7 patients with genotypic resistance to NNRTIs, 6 had NNRTI phenotypic resistance. Of the 5 patients with genotypic PI resistance, 5 had PI phenotypic resistance.
Of the 49 blood samples from chronically infected patients with genotypic resistance, 40 had NRTI genotypic resistance, but 6 samples had NRTI phenotypic resistance. 7 samples had NNRTI genotypic resistance, but 5 had phenotypic resistance. 13 samples had PI genotypic resistance, but 5 had PI phenotypic resistance. The study authors suggested that the lower incidence of phenotypic resistance in newly infected patients with genotypic resistance could be due to absence of drug pressure from not being on drugs. The authors suggested that genotypic testing may provide a better estimate of the amount of resistant virus transmitted to drug naive individuals.
Genotypic Resistance Prevalence Trends in the USA
Researchers from Stanford and Quest Labs have collected a database of 42,500 blood samples from patients. This study looked at the change in genotypic resistance seen in the first half of 1998 to 2001. They reported that resistance to NRTIs peaked during the first quarter of 1999 (74% resistant to at least 1 NRTI) and then declined to 58% at the end of 2001. NRTI cross-resistance due to TAMS (3 or more nuke mutations) also declined but was still seen in 25% of samples. The MDR Q151M or 69 declined from 1.7% to 0.5%. There was no change in NNRTI resistance as it remained above 40%. The PI resistance trend was similar to the NRTIs, peaking in the fourth quarter of 1998 at 54% and declining to 33%. The frequency of multi-class (PI+NRTI+NNRTI) resistance gradually declined from 26% to 17%. The study authors suggested that the decline in genotypic resistance since 1998 might reflect changing resistance test ing patterns -- an increase in resistance testing of naive patients; or possibly a decline in genotyping of treated patients due to more effective HAART therapy. Several researchers at the Seville meeting cautioned against reading too much into the trends in several of the studies presented here showing a steadying or reduction in the prevalence of resistant virus. One possible contributing factor, if this trend is true, is that HIV treatment has improved and so there is less drug resistance and less transmission of drug resistance.
Trend in Resistance in USA in Newly Infected
This report at Seville was from Susan Little (UCSD) on the trends in transmitted drug resistance by genotype & phenotype in recently infected individuals between 1995 and April 2002 in North America. This study compared the prevalence of transmitted drug resistance in 122 patients identified between June 2000 and March 2002 (period C) and 387 patients previously described (1995-May 2000). Transmitted drug resistance was compared between 3 time frames: period A= 1995-1998 (n=264); period B= 1999 - May 2000 (n=123); and period C= June 2000 - March 2002 (n=122).
The proportion of patients with resistance to one or more ART drugs did not change significantly between period B and C (12% vs 6.6%, p=0.13), following an increase between period A & B (3.4% vs 12%, p=0.001). The amount of NNRTI transmitted resistance remained the same from period B to C (7.3% to 6.6%, p=1.00) and comprised most of the transmitted resistance. In contrast, transmitted NRTI resistance decreased from period B to C from 5.7% to 0.8%), and for PI resistance from 8.1% to 0%). Multi-drug resistance decreased between B & C from 6.5% to 0.8%.
Since the amount of NNRTI drug transmitted resistance remained the same in the 2 US studies perhaps the reduced drug resistance transmitted is due to better adherence leading to less treatment failure & thus less drug resistance; and less use of protease inhibitors.
Decline in Transmitted Drug Resistance in Montreal May Be Tied To Improved Treatment
Pretreatment blood samples, collected between May 1996 and December 2001, from 148 newly infected individuals were genotypes and phenotyped. The percentage of 3100 chronically infected patients receiving treatment before and after June 2000 was obtained from 2 HIV clinics where it's estimated 50% of the total Montreal HIV population receive HIV care.
81% of patients (n=91) who had any genotype mutation (NRTI, NNRTI, or primary or secondary PI) before June 200 and 57% (n=20) after June 2000. The presence of primary NRTI and PI mutations was 23% (n=26) before and 11% after June 2000 (p=0.09). There was a decline in MDR from 4.1% to 0%. They reported that they observed the decrease in drug resistant transmitted virus paralleled an increase in the frequency of use of antiretroviral therapy among chronically infected in Montreal.
Prevalence of Multi-Drug Resistance in Treated Patients in France
This study (ANRS AC11 Resistance Study Group & B Masquelier) evaluated the prevalence of patient blood samples with multi-drug resistance (MDR) to at least 2 classes of currently available antiretroviral drugs (ARV) in treated patients in France.
Genotypic resistance was performed in June 2001. 17 centers participated and 456 genotypes were analyzed. 41% had no MDR; 34% had resistance to 1 class of ARV; 19% had MDR to 2 classes of ARV; and 6% had MDR to 3 classes of ARV. 4.5% of treated patients with detectable HIV viral load had MDR to 2 or 3 classes of drugs. Among the 115 patients with resistant virus to at least 2 classes 38% had viral load >30,000 and 40% had CD4 <200. Among these 115 patients 94% had class resistance to NRTIs, 88% to NNRTIs, and 59% to protease inhibitors. 15% of patients with NRTI resistance had the Q151M mutation, not a nice MDR mutation to have. The authors are evaluating how many of these patients are sensitive to abacavir, tenofovir, Kaletra and amprenavir/ritonavir, and to at least two available drugs. The authors estimated that based on these numbers from June 2001 between 1500 and 2000 patients on ARV with incomplete suppression have MDR to 3 classes of drugs, and need new drugs targeting other steps in the HIV replication process.
Response to Therapy By Patients in France Newly Infection with Genotypic Resistance, and Prevalence of Resistance Unchanged
Blood samples from 251 untreated newly infected patients were tested for genotypic resistance during acute infection. The study was conducted in France during 1999-2000 (ANRS AC11 Resistance Group, Cohort Primo, Primoferon, Primstop Study Groups). Patients were mostly infected by sex not IVDU. The average viral load was 5.43 log (269,000) viral load and 500 CD4s. 10% (25/251) of patients had genotypic resistance mutations associated with at least 1 antiretroviral drug. 19 (8%) patients had NRTI resistance; 10 (4%) of patients had NNRTI resistance. Primary resistance mutations to protease inhibitors were found in 5% (13/251). 12 patients (5%) had multidrug resistance mutations associated with 2 or 3 classes of antiretroviral drugs.
Patients with 1 or more key mutations had significantly lower viral load than patients without key mutations (95,000 vs 288,000). Of the 25 patients with genotypic mutations, 19 started multi-drug therapy. Patients with resistance to at least 1 drug of their current regimen had less decrease in their viral load at month 3 on therapy than patients with no resistance to their current therapy (-2.46 log vs -3.88 log). The authors reported that the prevalence of resistant virus with at least 1 key mutation was not different than found in the Primo cohort of patients in 1996-1999.
Drug Resistance in Naive Patients in Belgium and Response to Therapy
93 blood samples were collected from 4 participating centers in 2000 in Belgium. 5% of samples had reduced sensitivity or resistance to at least 1 nuke, 7.5% to NNRTIs, and 49% to protease inhibitors. For PI, the authors said this was entirely based on secondary mutations. Of the patients with 1 year followup 16% had virologic failure. Although the prevalence of patients with resistance mutations was substantial, only treatment with NRTIs for which the virus was resistant was significantly associated with treatment failure. So, these authors did not see significant treatment failure despite the presence of resistance mutations. However, several other studies have reported seeing reduced response to therapy when patients have pre-existing drug resistance.
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