Primary drug resistance has limited effect on disease progression and response to treatment

Patients infected with a drug-resistant strain of HIV do not experience faster disease progression or an impaired response to first-line HIV treatment, according to a long-term cohort study presented in the 1^st January edition of AIDS. However, the study did find that CD4 cell counts in the first year after infection fell more rapidly in patients with resistant virus, but not thereafter.

Experts estimate that around 10 to 20% of people infected with HIV contract a strain of the virus that is already resistant to one or more HIV drugs. This is called ‘primary resistance.’ The impact that this has on the progression of HIV disease and on response to treatment remains uncertain.

To gain more information on the impact of primary resistance, researchers from ‘Concerted Action on SeroConversion to AIDS and Death in Europe’ (CASCADE) analysed their data to work out whether resistance affects the CD4 cell count decline before HIV treatment is begun and the time to suppression of HIV levels following treatment initiation. CASCADE consists of 22 cohorts of patients in ten European countries, Australia and Canada for whom the date of seroconversion can be estimated reliably.

Their analysis included 300 patients who were recruited between 1987 and 1993, with resistance tests carried out within 18 months of infection. Twenty-nine (10%) of the patients were infected with HIV that had ‘intermediate’ or ‘high-level’ resistance to one or more antiretroviral drugs. Most of the patients were gay men, with an average age of 34 years.

The patients with drug resistance had higher CD4 cell counts after infection (median 698 vs. 604 cells/mm³), but this was not statistically significant (p = 0.14).

In the first year of infection, the rate of CD4 cell count decline was greater in the patients with transmitted drug resistance (p = 0.005), but there was no significant difference in the remaining four years of the study (p = 0.32). At the end of the five-year follow-up, the two groups’ median CD4 cell counts were similar.

The lack of a dramatic effect of primary resistance on disease progression may be due to the body’s immune response to HIV being unaffected by minor differences in fitness caused by the mutations.

“Small fitness differences between viruses may not play a major role in the subsequent pathogenic process,” the researchers write. “It is difficult to provide a hypothesis to explain our observation, other than to note that some form of immune homeostasis may be responsible for the CD4 cell count adjustment over the first year following infection.”

Resistance had little effect on the response to HIV treatment. In a multivariate analysis, patients with less than three active drugs in their treatment regimen had a similar chance of achieving a viral load below 500 copies/ml over a median of 397 days’ follow-up than those without primary resistance (p = 0.60). The patients’ HIV treatment regimens were not chosen based on their resistance test results.

The only factor that was significantly associated with treatment response was starting HIV treatment in or after 2000 (p = 0.001). This may reflect improvements in HIV treatment over time.

To confirm their findings, the investigators repeated their analysis using a less strict definition of ‘resistance’ and using a mathematical correction for the time delay between viral load measurements. Neither factor affected their conclusions. The use of sub-optimal HIV therapy by 18 patients before starting a highly active antiretroviral therapy (HAART) regimen also had no effect on the study’s overall findings.

Although their results are surprising, the investigators predict that differences between patients with and without primary resistance may emerge at later stages of HIV therapy. “These observations suggest that transmitted drug resistance impacts on response to first-line therapy in a subtle manner, if at all, and that longer term follow-up, and the study of second-line and salvage therapy will be required to identify clear correlates with the initial presence of resistance,” the researchers explain.

This study represents the longest follow-up of individuals with primary resistance published to date. However, its results are limited by the low number of patients included and the inability of the researchers to assess the impact of individual resistance mutations on treatment response.

The investigators write, “we are mindful of the relatively small number of patients infected with resistant virus in our study, and that our observations require confirmation. Nevertheless, the strength of our data is based on what is one of the longest follow-up periods for such individuals.”

They also point out that not all drug-resistant viruses are similar. They cite the recent case of a New York man who experienced very rapid HIV disease progression following infection with HIV that was resistant to drugs in all three major classes, with his CD4 cell count falling by 800 cells/mm³ over 20 months.

This cohort included two patients with triple-class resistance who had average CD4 cell count declines of 289 and 163 cells/mm³ in the first year after infection, similar to the average rate of 199 cells/mm³ in the patients with primary resistance. "The very fast progressor previously identified by Markowitz et al. is not necessarily representative of this population," the investigators write.