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Acute HIV infection:
Transmitted Resistance in Newly Infected Patients
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Report from 14th CROI, Feb 25-28, 2007, Los Angeles
Charles Hicks, M.D.
Associate Professor of Medicine
Duke University Medical Center
Wheeler et al. Abstract 648.
Data collected by the Centers for Disease Control and Prevention (CDC) assessed rates of transmitted HIV drug resistance among persons with newly diagnosed HIV infection between March 2003 and October 2006 via the Variant, Atypical, and Resistant HIV Surveillance System (VARHS). A total of 3130 genotypic sequences from persons having non-anonymous HIV testing at 409 testing sites in 11 locations (Colorado, Illinois, Louisiana, Maryland, Massachusetts, Michigan, Mississippi, North Carolina, South Carolina, Seattle Washington and Virginia) were identified. Sites collecting samples included sexually transmitted disease clinics (33%), publicly funded HIV counseling and testing sites (25%), private physician offices (8%), and hospital laboratories (7%). Overall, the group tested was 24% female, mostly aged 25-44 years (61%), and racially mixed - about half were African-American, and a quarter Caucasian. Half acquired HIV infection as men who have sex with other men (MSM) and about 20% listed heterosexual intercourse as their risk factor for HIV infection. Using the August 2006 International AIDS Society-USA (IAS-USA) Resistance Guidelines to define the presence of resistance, overall 10.4% of viruses tested showed evidence of drug resistance, with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) being most common (6.9%). Resistance to more than one class of drugs (termed multi-drug resistance - MDR) was seen in less than 2% of viruses. The rates of resistance did not differ significantly for various subgroups (i.e, women vs. men; MSM vs. heterosexuals, or among different racial/ethnic groups). The range of transmitted resistance varied between 8.5% and 13.0% for various geographic regions.
Eshleman et al. Abstract 650.
A second study (EXPLORE) investigated rates of resistance in viruses isolated from 195 MSM with recent or acute HIV infection. In this group, there were 31 viruses with any detectable resistance (15.9%) including 7 (3.6%) with MDR resistance and 3 (1.5%) with resistance to 3 classes of antiretroviral agents. In this population, resistance to nucleoside reverse transcriptase inhibitors (nRTI) was most common (8.7%) followed by NNRTI (6.7%), and protease inhibitor (PI) resistance (5.6%).
Low et al. Abstract 651.
A third study done in New York City assessed resistance among viruses infecting 108 persons diagnosed with acute or recently acquired HIV infection between January 2005 and December 2006. All but three persons studied were male. Rates of resistance in this population were compared to a similar group diagnosed in 2003-04. Interestingly, transmitted resistance declined between the two periods from 27.1% to 12.8% (a significant decline: p=0.02) with corresponding declines in NNRTI resistance (13.4% to 9.3%) and in MDR resistance (9.8% to 4.6%).
Zetola et al Abstract 652.
Declining rates of transmitted resistance were also seen in a population in San Francisco studied between 2004 and 2006. This group was comprised of newly diagnosed persons from STD clinics, from persons who sought HIV testing at a counseling and testing center, and from a research cohort of patients with acute HIV infection. A total of 55 viruses with resistance were identified from 402 persons with a new diagnosis of HIV infection (13.7%). Again, NNRTI resistance was most common - 9.5% and just over 3% of viruses had MDR resistance including three with resistance to three classes (0.7%). Rates of detected resistance declined over the period of observation, being lower in persons diagnosed in 2006 than in 2005.
Para et al. Abstract 653.
Data from a research study testing an HIV vaccine (the gp120 vaccine) that enrolled 5095 volunteers included a total of 362 persons who became HIV infected during the vaccine trial. Of these, 253 infecting viruses were able to be sequenced for genotypic resistance testing. Forty (15.8%) had at least one resistance mutation including 14 (5%) with MDR resistance. Rates of resistance to various drug classes in this population were quite similar (nRTI - 10%; NNRTI - 8%; PI - 8%)
De Mendoza et al. Abstract 656.
Finally, a Spanish study demonstrated that transmitted resistance is an issue of international significance. Among persons diagnosed as recent HIV seroconvertors between 1997 and 2006, 14.7% were infected with viruses containing resistance to at least one HIV drug. The duration of the study permitted an analysis of changes in transmitted resistance over time. Rates of transmitted resistance increased between 2000 and 2006, going from 5.3% in 2000-01, to 10.7% between 2002-04, to 14.7% between 2005-06. Surprisingly, resistance was most common between 1997 and 1999, being detected in 29% of viral isolates identified during this period. One reason why this might be so is that treatment combinations widely used during this period had relatively low levels of virologic suppression and often generated transmissable resistance when suppression was not achieved.
Summary - Transmitted resistance in the resource-rich parts of the world appears to be a significant and ongoing problem with most cohorts reported revealing rates of resistance around 10% or so. This is clearly substantial and when a broader range of different patient types is represented, rates of resistance do not appear to differ meaningfully among the various groups. The studies presented at this meeting appeared to show that rates of resistance were not continuing to increase as some had feared with earlier reports. Nonetheless, the recommendation to complete genotypic resistance testing for all patients prior to initiating antiretroviral therapy seems well-founded. Failure to identify pre-existing resistance changes will lead to higher rates of treatment failure when drugs affected by the resistance mutations are used. Given the popularity of NNRTI-based treatment as initial therapy, the fact that NNRTI resistance is frequently the most commonly observed type of resistance transmitted in particularly relevant.
Miscellaneous Issues in Acute HIV Infection
Aseptic Meningitis as an Indicator Condition for Acute HIV Infection.
Hanson and colleagues studied a group of patients who had residual samples of cerebrospinal fluid (CSF) saved following testing for herpes simplex virus (HSV) at the Duke University Medical Center microbiology laboratory during the period January 1999 to December 2004. From among a larger group of samples, 57 patients were identified whose clinical characteristics and laboratory findings were consistent with a diagnosis of acute aseptic meningitis. Using a sample pooling technique that tested for HIV RNA in the CSF of this population of patients, 3 cases of previously undiagnosed HIV infection were found. Two of the three cases had high levels of HIV detected in the CSF (consistent with acute HIV infection) and both had been evaluated in the Emergency Department (ED) for symptoms suggestive of acute HIV infection. The third patient was more seriously ill and was admitted to the hospital. His blood cultures subsequently grew Streptococcus pneumoniae and he ultimately did not survive the hospitalization. The level of virus in his CSF was much lower than that seen in the other two patients and he likely was not in the midst of the acute HIV infection period. All three of the patients presented to the emergency department for care at the time that the CSF was obtained. Overall, then, more than 5% of these patients who had a diagnosis of acute aseptic meningitis that prompted a lumbar puncture and testing for HSV infection were ultimately determined to be HIV-infected. WhatÕs more it appeared that the acute HIV infection syndrome was the proximate cause of the symptoms in two of the three cases. Thus, if we are do diagnose this group correctly and promptly, an approach that uses nucleic acid amplification testing of plasma (such as HIV RNA PCR testing) is essential. Among the many causes of aseptic meningitis, HIV infection represents one of the few diagnoses with significant treatment implications. Testing of all patients who have aseptic meningitis as defined by symptoms and laboratory findings with an HIV RNA PCR seems warranted. While there are significant challenges to doing this type of testing in emergency departments, recent recommendations from the CDC to expand HIV testing would appear to be particularly relevant to emergency and acute care settings.
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