TB leads to poorer CD4 cell gains after starting HIV treatment

Tuberculosis (TB) is associated with an impaired immune response to antiretroviral therapy, according to Italian research published in the online edition of Clinical Infectious Diseases.

The study involved patients starting HIV therapy for the first time. Individuals with TB had lower CD4 cell gains when compared to individuals with other AIDS-defining illness and patients who were AIDS-free. This was possibly because individuals with TB were also less likely to achieve virological suppression.

“HIV-infected patients starting cART [combination antiretroviral therapy] when ART naïve and with a tuberculosis diagnosis have an impaired immune recovery,” write the authors. “This impairment seems to persist over 3 years…and is mainly explained by differences in the level of viral suppression between patients with and those without tuberculosis.”

Worldwide, TB is the single biggest cause of serious illness and death in patients with HIV.

Antiretroviral therapy has transformed the prognosis of many HIV-positive patients, which is now considered normal. Starting HIV treatment normally achieves suppression of viral load to undetectable levels and an increase in CD4 cell count.

Factors associated with a poorer immunological response to treatment are poorly understood and studies exploring the significance of TB to CD4 cell gains after starting treatment have produced contradictory results.

However, there are two theoretical mechanisms which mean that individuals with TB have could have lower increases in CD4 cell count. First, TB can contribute to the death of immune cells. Second, the infection can be difficult to manage in patients treated with antiretroviral drugs.

Italian investigators wished to establish a better understanding of the interaction between TB and immune restoration after starting antiretroviral therapy. They therefore designed a study involving  6528 patients who initiated treatment between 1996 and 2010.

The patients were divided into three categories according to their TB and AIDS status when HIV treatment was started:

• TB – 2%.

• Other AIDS-defining illness – 16%.

• Neither TB nor AIDS – 82%.

The investigators then calculated the time taken for patients in each group to experience an increase in CD4 cell count of 100, 200 and 300 cells/mm³ above baseline and to a CD4 cell count of 500 cells/mm³ or more. The time between starting treatment and suppression of viral load to below 50 copies/ml was also assessed.

Median baseline CD4 cell count was 269 cells/mm³ and almost two-thirds (64%) of patients started HIV therapy when their CD4 cell count was below 350 cells/mm³, the current European threshold for the initiation of therapy.

The 125 patients who had TB had this infection diagnosed a median of one week before they started HIV treatment. The 1061 individuals with another AIDS-defining condition had this detected a median of four days antiretroviral therapy was prescribed.

Compared to patients without AIDS, individuals with TB were significantly younger, had a lower baseline CD4 cell count and were less likely to be born in Italy (all p < 0.001).

Overall, CD4 cell count increased by 100 cells/mm³ a median of eight months after treatment was started. The median time to an increase of 200 cells/mm³ was 18 months, and it took a median of 34 months for CD4 cell count to increase by 300 cells/mm³. Twenty-four months after treatment was started, 55% of patients had a CD4 cell count above 500 cells/mm³.

After controlling for pre-treatment CD4 cell count, the investigators found that patients with TB had a significantly lower chance of immune recovery when compared to patients without AIDS, regardless of which CD4 cell threshold was used (above 200 cells/mm³, p = 0.02).

Individuals with TB were also less likely to achieve an increase in CD4 cell count of 200 or 300 cells/mm³ compared to patients with another AIDS-defining condition (p = 0.05 and p = 0.02 respectively).

However, neither TB nor other AIDS-defining illnesses significantly reduced the chances of CD4 cell count increasing to above 500 cells/mm³.

Infection with TB also appeared to affect the chances of suppressing viral load to undetectable levels.

A viral load below 50 copies/ml was achieved at some point by 74% of patients. It took patients with TB a median of 20 months to suppress viral load, compared to a median of 15 months for those with another AIDS-defining illness and 14 months for individuals free of TB and AIDS.

Further analysis found a non-significant association between taking HIV therapy and TB treatment together and a reduction in the odds of achieving an undetectable viral load (p = 0.09).

“HIV and tuberculosis coinfection is characterized by several challenges in terms of patient management, such as poor adherence and overlapping toxicities,” note the authors. “In addition, interactions with antituberculosis treatment may cause reduced plasma concentrations of antiretrovirals, resulting in a reduced chance of virological success.”

They conclude, “our analysis showed that HIV-infected patients starting cART when ART naïve and with a tuberculosis diagnosis have an impaired immune recovery with cART, mainly because of differences in levels of viral suppression between them and both patients with nontuberculosis AIDS and those without AIDS.” They call for further research exploring interactions between the two therapies.