Tropism impacts on virological success of first-line HIV therapy

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HIV tropism has a significant impact on the virological success of first-line antiretroviral therapy, a Spanish study published in the July 1st edition of the Journal of Infectious Diseases suggests.

Individuals whose HIV used the CXCR4 co-receptor were significantly less likely to achieve an undetectable viral load than patients whose virus used the CCR5 co-receptor. The association between the CXCR4 co-receptor and poorer outcomes was especially strong in patients infected with HIV subtype B.

In this study patients were receiving treatment with tenofovir/FTC (Truvada) and either nevirapine or atazanavir/ritonavir. No patients received a drug from the CCR5 inhibitor class.



In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 


When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).


A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.


In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.


In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

“It may be worthwhile to perform baseline viral tropism testing before beginning any antiretroviral regimen,” comment the investigators.

HIV uses a co-receptor to latch onto CD4 cells.

In the earlier stages of infection, virus using the CCR5 co-receptor predominate, whereas virus utilising CXCR4 tends to be associated with the later stages of HIV infection.The preference for a receptor type is called tropism, and can be determined by tropism testing.

In patients who are not taking antiretroviral treatment, the presence of CXCR4 virus has been associated with faster disease progression. Tropism testing is recommended before starting treatment with the CCR5 inhibitor maraviroc (Celsentri), the only licensed drug in this class of antiretroviral.

However, the impact of co-receptor tropism on the outcomes of first-line HIV treatment that does not contain a CCR5 inhibitor is largely unknown.

Investigators from the Hospital Carlos III in Madrid therefore performed a retrospective study involving treatment-naïve patients who were enrolled into a randomised study. This was designed to compare the efficacy of therapy based on atazanavir (Reyataz) boosted by ritonavir (Norvir) with treatment including nevirapine (Viramune). The patients also took Truvada (FTC/tenofovir), and results showed that the combinations were equally effective.

Blood samples obtained at the start of therapy were tested to determine which co-receptor was used by patients’ virus.

Changes in viral load and CD4 cell count after six and twelve months of treatment were compared according to co-receptor.

A total of 569 patients were randomised and 428 completed 48 weeks of treatment.

Virus using the CXCR4 co-receptor was found in 14%, and 22% of individuals were infected with a non-subtype B strain of HIV.

At baseline, patients with CXCR4 virus had significantly higher viral load (5.4 vs. 5.2 log10 copies/ml; p =0.044) and lower CD4 cell counts (145 vs. 188 cells/mm3; p < 0.001) than individuals with virus using the CCR5 co-receptor.

After a year of therapy, patients with CXCR4 virus were significantly less likely than individuals with CCR5 virus to have an undetectable viral load (77% vs. 92%; p = 0.009).

This association between the CXCR4 co-receptor and poorer virological control at week 24 (p = 0.012) was confirmed in multivariate analysis.  There was also a trend towards poorer treatment response at week 48.

It is harder to isolate HIV tropism in patients with non-B subtypes. Therefore the investigators performed further analysis, which was this time restricted to individuals with HIV subtype B.

This showed a strong association between the CXCR4 co-receptor and poorer virological control at both week 24 (p = 0.001) and week 48 (p < 0.001).

“When we limited our analyses to participants infected with clade B viruses, the strength of the impact of viral tropism on virological response was more robust than in the whole study population,” observe the authors.

Unlike some other research, there was no evidence that the CXCR4 co-receptor had a negative impact on CD4 cell recovery.

“In antiretroviral-naïve patients beginning antiretroviral therapy, baseline HIV-1 tropism seems to be an independent predictor of virologic response,” conclude the investigators, adding “this observation may have important clinical implications for the monitoring of antiretroviral therapy and interpretation of comparative trials.”


Seclen E et al. Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy. J Infect Dis 204: 139-44, 2011 (click here for the free abstract).