Sub-type C infection does not increase the risk of virologic failure when people are taking tenofovir-containing first-line ART

There is no evidence that HIV-positive people with sub-type C infection have an increased risk of treatment failure when receiving tenofovir-containing regimens, investigators from the UK report in the online edition of the Journal of Infectious Diseases. Investigators monitored over 8000 people initiating standard first-line tenofovir-containing regimens and found that after adjustment for demographic and clinical factors, people with sub-type C infection were no more likely to experience virologic failure than those with sub-type B infection.

“These observations may imply there is no intrinsic effect of viral subtype on the efficacy of tenofovir-containing regimens, and specially alleviate concerns that efficacy would be compromised for subtype C infections,” write the authors. “This is a reassuring finding in light of the rapid worldwide expansion in the prescribing of tenofovir and supports WHO recommendations that this is an appropriate first-line drug, even in geographical regions where subtype C HIV-1 infection is endemic.”

Some research has shown that tenofovir-containing regimens have reduced efficacy in people with sub-type C infection. It has been suggested that this is because sub-type C is especially likely to develop the K65R resistance mutation, which is selected by tenofovir. If this is the case, it could have serious public health implications. Approximately 50% of people living with HIV worldwide have sub-type C infection and since 2013 World Health Organization (WHO) guidelines have recommended tenofovir for first-line antiretroviral therapy.

With these concerns in mind, a team of investigators analysed and evaluated whether HIV-1 sub-type influenced virologic outcomes in people starting standard first-line HIV therapy containing tenofovir. The study population comprised 8746 individuals enrolled in the UK Collaborative HIV Cohort Study (www.ukchic.org.uk).

People were eligible for inclusion if they initiated a first-line regimen that contained tenofovir, plus emtricitabine or lamivudine, with either a non-nucleoside reverse transcriptase inhibitor (NNRTI – efavirenz or nevirapine) or a ritonavir-boosted protease inhibitor (lopinavir, atazanavir or darunavir).

Virologic failure was defined as two consecutive viral load measurements above 200 copies/ml in a six-month period after suppression of viral load. The investigators took into account other factors associated with treatment outcomes – type of therapy, HIV risk group, baseline CD4 and viral load – to see if sub-type really did influence the risk of virologic failure.

Sub-type was determined in 6149 people. Approximately two-thirds (n = 4123) were infected with sub-type B, 823 people with sub-type C and 1203 were infected with non-B/C sub-types.

There were significant demographic differences according to sub-type. People infected with sub-type B were predominantly white (83%) and gay men (85%), whereas people with sub-type C infection were mainly black (70%) and heterosexual (79%).

Individuals were followed for a median of 3.3 years. During this time, virologic failure was observed in 6% of people with sub-type B infection, 10% with sub-type C infection and 9.5% with non-B/C sub-types.

This meant, that in unadjusted analysis, the rate of treatment failure was approximately twofold higher in people with sub-type C compared to those with sub-type B (B vs. C, HR = 0.54; 95% CI, 0.43-0.67; p < 0.001). Outcomes were comparable for people with sub-type C and non-B/C sub-types.

However, after adjustment for demographic and clinical characteristics, the difference in outcomes between people with sub-type B and sub-type C infections ceased to be significant (HR = 0.87; 95% CI, 0.63-1.21; p = 0.41). Comparison between C and non-B/C sub-types was unchanged.

Examination of the reasons for the change between the unadjusted and adjusted models showed that the most important factors were HIV risk group (lower rate of virologic failure in gay men) and ethnicity (lower rate of virologic failure among white and Asian people). Regimens based on NNRTIs were more durable than protease inhibitor-containing combinations. Virologic failure was more common in people with a baseline CD4 count below 100 cells/mm³ and also in individuals with a baseline viral load above 100,000 copies/ml.

Genotypic resistance test results were available for 41% of those who experienced virological failure. Tenofovir-associated resistance mutations (mainly K65R) were more common in people with sub-type C virus than in those with sub-type B or nonB/C viruses (22.7% vs 6.1% and 8.1%; p = 0.003).

“In the present study patients with HIV-1 subtype C infection on a first-line tenofovir-containing regimen experienced a higher rate of virological failure than patients with subtype B virus,” comment the investigators. “However, this effect was almost entirely explained by differences between groups in demographic and clinical characteristics.”

They suggest that adherence is a likely explanation for the differences in outcomes between risk groups.

The authors of an accompanying editorial were reassured by the findings of the study as they show that WHO treatment guidelines for the treatment of sub-type C infection do not need to change. However, they conclude, “it is of utmost importance to globally improve treatment conditions so that adherence problems and treatment failures can be identified early.”