New resistance becoming rarer as more patients achieve undetectable HIV viral load

There has been a drastic fall in the incidence of new cases of drug-resistant HIV amongst patients taking antiretroviral therapy in the Canadian province of British Columbia.

In the January 1^st edition of Clinical Infectious Diseases investigators report that the incidence of newly detected resistance fell twelve-fold between 1996 and 2008.

“There has been a drastic decrease in the incidence of new cases of HIV-1 drug resistance, despite increases in annual (and, especially, cumulative) exposure to antiretrovirals”, write the investigators. They also note “this has occurred alongside a steady increase in the proportion of patients achieving virological suppression.”

Since combination antiretroviral treatment became available, there has been a steady and sustained fall in rates of illness and death in people with HIV.

However, it is possible for HIV to become resistant to the drugs used to treat it and this can compromise the effectiveness of antiretroviral treatment. Reasons for this can include sub-optimal treatment strategies, poor patient adherence to therapy, interactions, and low levels of medicines in the blood.

In recent years potent, safe and easy to take anti-HIV drugs have become available, some of which work against the virus in novel ways. These newer agents provide important options, especially for those who have extensive experience of HIV treatment. Antiretroviral treatment guidelines therefore state that an undetectable viral load should be the aim for all patients taking anti-HIV drugs.

Numerous studies have looked at the prevalence of drug-resistant HIV. However few have analysed the incidence of new cases of resistance amongst patients taking HIV treatment. The one study that has, found that this fell over time.

Investigators therefore examined viral load and resistance data for 5422 individuals who started antiretroviral therapy in British Columbia between 1996 and 2008.

Also calculated was the proportion of patients suppressing their viral load to undetectable levels and the incidence of resistance to each of the three main classes of antiretroviral drugs - nucleoside reverse transcriptase inhibitors (NRTIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors.

The number of patients with newly detected resistance fell dramatically year on year from a peak of 571 in 1996 to 71 in 2008.

The investigators emphasise that these falls occurred “despite increased exposure to antiretroviral therapy”. Indeed high levels of resistance in 1996 occurred despite only 39,200 person-months of exposure to antiretroviral treatment. By contrast, the massively reduced incidence of new resistance in 2008 occurred against a background of cumulative exposure to HIV treatment amounting to 461,787 person-months.

Only 14 cases of new resistance to protease inhibitors were detected in the entire province of British Columbia in 2008, “despite over 30,000 person-months of protease inhibitor therapy in 2008 and a cumulative total of over 269,000 person-months by the end of 2008.”

The incidence rate for new cases of resistance fell twelve-fold from 1.73 cases per 100 person-months in 1997 to just 0.13 cases per 100-person months in 2008.

This fall was seen across the three main classes of antiretrovirals. The incidence of new resistance to NRTIs fell by 50% within three years, with incidence of resistance to NNRTIs falling by 50% in 2.5 years, and by 50% within two years for protease inhibitors.

Moreover, the investigators observed individual resistance mutations were also, for the most part, becoming less common.

“Decreases in the incidence of resistance can be partially explained by higher rates of virological suppression over time”, write the authors.

In 1996, the median lowest viral load amongst patients taking antiretroviral therapy was 3.76 log₁₀, but by 2007 lowest median viral load had fallen to below 50 copies/ml.

Moreover, the proportion of patients with a viral load below 50 copies/ml increased linearly overtime from 65% in 2000 to 87% in 2007 (p

“Improvements over time in HAART [ highly active antiretroviral therapy], including the periodic introduction of new therapeutic agents and the continual assessment of and improvement in how those agents are prescribed, have most likely contributed to decreases in the incidence rate of detection of HIV-1 drug resistance”, suggest the authors.

Older drugs from the NNRTI class (efavirenz and nevirapine) are the antiretroviral agents most vulnerable to resistance. “However even for this drug class”, write the investigators, “the decrease in resistance incidence has been remarkable, with an over 40-fold decrease in NNRTI resistance per 100 person-months of NNRTI exposure from 1996 to 2008.”

The authors believe that their findings are highly significant.

“Efforts to improve accessibility to HAART have the potential to greatly reduce HIV-1 levels in populations without increasing the risk of drug resistance”, they conclude, “if current trends persist, the continued improvement of HAART and the increased availability of new drugs could potentially make the development of new HIV drug resistance a rare event.”