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Randomised trial of ART in TB patients with high CD4 counts

<p><strong>Nathan Geffen</strong></p>


October 10, 2011

The benefits of initiating antiretroviral treatment (ART) in TB co-infected patients with CD4 counts below 350 cells/mm3 have been demonstrated in a number of recent studies. [1-2]

Now an open-label randomised controlled trial by Nanteza and colleagues has been published that looks at patients with higher CD4 counts. The trial, run in Uganda, compared 6 months of ART concurrent with TB treatment versus only TB treatment in patients with CD4 counts > 350 cells/mm3. The trial was small, but it provides some evidence that there is clinical benefit to placing patients with high CD4 counts on ART. [3]

From October 2004 through September 2008, 4,951 people were screened. Of these 250 patients co-infected with TB and HIV and with CD4 counts >350 cells/mm3 were enrolled. Of these 232 were randomised and 214 remained on the trial and eligible for analysis. The final control and intervention arms each had 107 patients. Patients in the intervention arm were given ART (abacavir, lamivudine and AZT) for six months. Participants were followed up for 24 months. The trial was designed and approved before several studies demonstrated that structured treatment interruptions are not a viable treatment option. The authors explained that the rationale of the study was that a punctuated course of antiretroviral therapy in patients with high CD4 cell counts would suppress viral replication during therapy for tuberculosis, block the effects of immune activation on T cells harboring HIV, slow the pace of HIV disease progression, and improve clinical outcomes.

The baseline characteristics of the patients were mostly well matched. There were slightly more men in the control arm (63% versus 52%). Nearly all patients had at least one TB symptom, especially cough. Median age was 31 years. Nearly 90% of patients were both smear and culture-positive. Interestingly 8% of patients were smear-positive and culture-negative, while only 3% were smear-negative and culture-positive. The intervention and control arms had similar median CD4 counts (between 500 and 550 cells/mm3) and median viral load (4.6 and 4.7 log10 copies/mL).

The primary endpoint was a composite of CD4 cell count <250 cells/mm3, clinical AIDS, or death. In the intervention arm, 17 people reached this endpoint versus 25 in the control arm (p=0.17). Most people reached the endpoint on the basis of CD4 count, 15 in the intervention arm and 18 in the control arm. They initiated lifelong ART. Although not statistically significant, there were consistently fewer endpoint events in the intervention arm throughout the trial. At 12 months of follow-up the difference between the arms reached significance (98% and 90%, respectively; p=0.02), but became non-significant by the end of the follow-up period.

There were two deaths in the ART arm and no clinical endpoints. There were three clinical endpoints and four deaths in the control arm. Despite the tiny numbers, this was significant (p=0.048).

In the intervention arm, 86% of participants achieved a viral load <400 copies/mL at three and six months. Viral load rebounded upon discontinuation of treatment to near baseline. The average viral load of the control group did not change significantly over the 24-month period.

There were 45 versus 28 adverse events in the control and intervention groups respectively. When considered individually, the risk of a grade 3 or 4 adverse event was 76% greater in the control arm than in the intervention arm (rate ratio, 1.76; 95% CI: 1.24–2.53). About half the adverse events took place during the six months treatment (ART or TB) stage of the study. Neutropenia was high and not significantly different in both arms (17 versus 25% in the intervention and control arms respectively). The authors therefore concluded that neutropenia is common in patients with tuberculosis, even when CD4 counts are >350 cells/mm3 and that treatment with concurrent antiretroviral therapy only partially mitigates the effect of HIV infection on bone marrow suppression. As would be expected in a trial of people with relatively high CD4 counts, no Immune Reconstitution Syndrome was detected.

No patients were culture-positive after six months of TB therapy. The average time to culture conversion was 37.5 days in the intervention group versus 29 in the control, but this was not significant (p=0.37).

The authors state that the trial provides limited further support for early initiation of treatment.

Comment

Although small and despite the outdated and short treatment intervention, this study does provide limited support for initiating all HIV-positive patients with TB on ART, even at high CD4 counts.

The World Health Organisation (WHO) recommends that treatment be provided to all patients with TB irrespective of CD4 count. The South African government has recently announced that it will treat all patients with CD4 counts <350 cells/mm3. This study offers some evidence, albeit not compelling, that South Africa should go further and implement the WHO recommendation. It seems likely that South Africa’s new HIV and TB National Strategic Plan for 2012-2016 will provide for this.

Also interesting was that in this Ugandan setting 25% of the TB and HIV co-infected patients who screened for the trial had CD4 counts above 350 cells/mm3.

In Khayelitsha, Cape Town, nearly one in five HIV-positive patients presents with a CD4 count >500 cells/mm3 (communication with MSF). These statistics show that the question of determining the optimal starting point affects many people and is an important one.

We look forward to the results of the TEMPRANO and START trials that have been designed to answer this question.

References:

1. Abdool Karim SS et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010; 362:697–706.

http://www.nejm.org/doi/full/10.1056/NEJMoa0905848

2. Blanc FX et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Vienna: International AIDS Society, 2010:284–5.

http://pag.aids2010.org/Abstracts.aspx?AID=17091

3. Nanteza MW et al. 2011. A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4+ T-cell counts ≥ 350 cells/µL. JID 2011:204 (15 September)

http://jid.oxfordjournals.org/content/204/6/884.abstract

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