MicrobiologyBytes

Drug-resistant HIV at levels too low to be detected by standard tests is not unusual and may contribute to treatment failure, according to new research. Mutations in the AIDS virus commonly occur during treatment, especially if HIV drugs are not taken consistently, and may cause treatments to fail. HIV treatment in developed countries normally includes testing for these mutations, both to select first-line drugs for a given patient and to choose second-line drugs if the virus rebounds from initial treatment. However, tests used by clinical laboratories cannot reliably detect mutant viruses that make up less than about 20% of the virus in a patient s blood. To investigate the role of resistant virus present at lower levels, researchers studied HIV from more than 500 recently infected patients in Canada and the US. Although these individuals had not received anti-HIV drugs, a highly sensitive test developed by the researchers showed that more than 10% carried HIV with common drug-resistance mutations that were not detected using usual tests. The researchers then studied 316 samples from a separate study of about 1400 patients who were started on their first HIV treatment, which included the drug efavirenz. Before starting treatment, none of these patients had resistance to efavirenz according to standard tests. However, highly sensitive testing showed that 7 of the 95 patients who experienced treatment failure had low levels of HIV with resistance mutations to efavirenz prior to treatment. Of 211 patients whose treatment did not fail, only 2 showed low level resistance prior to treatment. These data suggest that sensitive testing for resistance could avert failures in HIV treatment. However, given the small number of cases in this initial study, larger studies are needed to confirm the results – although a sizable proportion of treatment naïve HIV infected individuals harbor a minority population of drug-resistant HIV, many patients with positive results on highly sensitive resistance testing might not go on to experience treatment failure.

Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. 2008 PLoS Med 5(7): e158
Since the mid-1990s, several powerful antiretroviral drug combinations have been developed that have greatly improved the prognosis of HIV infection. All antiretroviral therapy (ART) regimens combine drugs that act against HIV in different ways (so-called different drug classes). Multiple drugs are necessary because HIV continually accumulates random changes (mutations) in its genetic material (genome). Some of these mutations make HIV resistant to individual antiretroviral drugs, so a mixture of drugs is needed to keep the virus in check. However, the efficacy of ART (which itself selects for drug-resistant variants by giving them a growth advantage over drug-sensitive variants) is substantially reduced when these variants account for more than about 20% of the viruses in an infected person. This level of variant virus can be detected in blood samples with a technique called bulk sequencing. In North America and Europe, where ART has been widely used for many years, around 20% of HIV-infected people who have taken ART themselves develop this level of drug-resistant virus, which can be transmitted by the same routes as nonresistant HIV (typically unprotected sexual intercourse or needle sharing). In such cases, the person acquiring drug-resistant HIV may experience treatment failure when drugs later fail to work against the resistant virus. In these countries, therefore, resistance testing by bulk sequencing is done routinely before ART is initiated to decide which antiviral drugs are likely to be effective.

Several years usually elapse between the time a person becomes infected with HIV and the time he or she starts ART. During this time, the absence of selection pressure from antiviral drugs means that transmitted drug-resistant variants tend to decline to levels undetectable by bulk sequencing. These ‘‘minority drug-resistant variants’’ can be detected using other more sensitive tests but it is not known what proportion of HIV-infected people who have never taken ART carry minority drug-resistant variants (the ‘‘prevalence’’ of these variants). It is also unknown whether the presence of minority drugresistant variants reduces the success of ART. In this paper, the researchers first report a ‘‘cross-sectional’’ study in North America using a sensitive assay to determine the prevalence of minority drug-resistant viruses among HIV-infected people who had never received ART. They then investigate whether minority drug-resistant variants have any impact on the effectiveness of ART in a ‘‘case-control’’ study.

In their cross-sectional study, the researchers used a highly sensitive test for detecting mutations (called a real-time PCR-based assay) to look for low levels of viruses carrying any of eight major drug-resistance mutations in people with newly diagnosed HIV infection who reported no prior treatment with ART. Seventeen percent of the people who had only wild-type (nonmutated) virus by bulk sequencing (205 participants) were found, in fact, to carry low levels of virus variants with 1–3 drug-resistance mutations; 2% of them carried viruses resistant to two different drug classes (called multi-drug resistance). Among the people with resistance mutations detected by bulk sequencing (303 participants), 10% had at least one additional minority drug-resistant variant, often a viral variant that was resistant to a drug class different from that detected by bulk sequencing. In the case-control study, the researchers used their sensitive assays to measure the levels of viruses containing any of the three most common drug resistance mutations likely to affect viral responses to the antiretroviral drugs efavirenz and lamivudine in 316 people just before they started their first HIV treatment, which included these drugs. Of people for whom ART failed, 7% were infected with minority drug-resistant virus variants at baseline compared with only 0.9% of people for whom ART worked; this difference was statistically significant.

The findings of the cross-sectional study indicate that conventional bulk sequencing fails to detect a large proportion of transmitted HIV drug resistance and suggest that the transmission of drug-resistant variants from infectious ART-experienced people to ART-naive individuals might not be uncommon. The findings of the case-control study suggest that the minority drug-resistant HIV variants may have clinical consequences. That is, the presence of such variants in individuals who have not previously taken ART may reduce the efficacy of some ART regimens. However, the number of participants meeting the criteria for analysis in the cross-sectional study was limited, and the association between minority resistance and treatment failure may have been influenced by other factors. Taken together, these findings suggest that, to ensure that first-line ART is as effective as possible, greater efforts should be made to prevent HIV transmission, whether from ART-experienced or ART-naive people. However, because data on minority drug-resistant virus are limited, more studies – particularly with recent populations – are needed before testing for these variants can be considered appropriate in the clinical management of newly diagnosed HIV infection.

Related:

• HIV treatment in Africa as successful as in Europe, if started in time
• Roche abandons HIV research
• Parasitic worm may increase susceptibility to AIDS virus

Tags: Biology, Health, HIV/AIDS, Medicine, Microbiology, Science, Virology

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