Date Published: November 2, 2011
Publisher: BioMed Central
Author(s): Sanjeev Sinha, Sahajal Dhooria, Sanjiv Kumar, Nipam Shah, T Velpandian, AK Ravi, Narendra Kumar, Hafeez Ahmad, Akshat Bhargwa, Karan Chug, Naresh Bumma, Rahul Chandrashekhar, Meera Ekka, Vishnu Sreenivas, Surendra K Sharma, JC Samantaray, Ronald Mitsuyasu.
Rifampicin reduces the plasma concentrations of nevirapine in human immunodeficiency virus (HIV) and tuberculosis (TB) co-infected patients, who are administered these drugs concomitantly. We conducted a prospective interventional study to assess the efficacy of nevirapine-containing highly active antiretroviral treatment (HAART) when co-administered with rifampicin-containing antituberculosis treatment (ATT) and also measured plasma nevirapine concentrations in patients receiving such a nevirapine-containing HAART regimen.
63 cases included antiretroviral treatment naïve HIV-TB co-infected patients with CD4 counts less than 200 cells/mm3 started on rifampicin-containing ATT followed by nevirapine-containing HAART. In control group we included 51 HIV patients without tuberculosis and on nevirapine-containing HAART. They were assessed for clinical and immunological response at the end of 24 and 48 weeks. Plasma nevirapine concentrations were measured at days 14, 28, 42 and 180 of starting HAART.
97 out of 114 (85.1%) patients were alive at the end of 48 weeks. The CD4 cell count showed a mean increase of 108 vs.113 cells/mm3 (p=0.83) at 24 weeks of HAART in cases and controls respectively. Overall, 58.73% patients in cases had viral loads of less than 400 copies/ml at the end of 48 weeks. The mean (± SD) Nevirapine concentrations of cases and control at 14, 28, 42 and 180 days were 2.19 ± 1.49 vs. 3.27 ± 4.95 (p = 0.10), 2.78 ± 1.60 vs. 3.67 ± 3.59 (p = 0.08), 3.06 ± 3.32 vs. 4.04 ± 2.55 (p = 0.10) respectively and 3.04 μg/ml (in cases).
Good immunological and clinical response can be obtained in HIV-TB co-infected patients receiving rifampicin and nevirapine concomitantly despite somewhat lower nevirapine trough concentrations. This suggests that rifampicin-containing ATT may be co administered in resource limited setting with nevirapine-containing HAART regimen without substantial reduction in antiretroviral effectiveness. Larger sample sized studies and longer follow-up are required to identify populations of individuals where the reduction in nevirapine concentration may result in lower ART response or shorter response duration.
There are 33.3 million people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) in the world . Out of these, around 40% of patients are co-infected with tuberculosis (henceforth, called HIV-TB co-infected patients), forming a total estimated co-infection prevalence of 13-15 million persons worldwide . As per the latest report by National AIDS Control Organization (NACO), the prevalence of HIV in India is 0.29% with a total burden of 2.27 million HIV-infected patients . NACO has a free antiretroviral therapy (ART) programme in place since April, 2004, which provides antiretroviral drugs in India according to the WHO guidelines . Nevirapine is frequently used in India in HIV/AIDS treatment as a component of first-line regimens, and nevirapine-based fixed-dose combinations (with zidovudine plus lamivudine or stavudine plus lamivudine). These drug combinations are modestly priced, do not require food restrictions, and are given as two tablets twice daily, ensuring good adherence [5-9]. Rifampicin is an important anti- tuberculosis drug and is usually administered for 6 to 8 months along with other anti- tuberculosis medications.
This was a prospective study conducted at the All India Institute of Medical Sciences (AIIMS), New Delhi between September, 2007 and March, 2011. Patients who tested positive for HIV by ELISA and were ART-naïve and presented with concomitant TB were enrolled as cases. Patients, who tested positive for HIV by ELISA, were ART-naïve and without TB were enrolled as controls. Only patients having CD4 count < 200 cells/mm3 and with normal renal and hepatic function (SGOT and SGPT ≤ 5 × upper normal limit, Serum Bilirubin ≤ 2.5 × upper normal limit and Creatinine ≤ 3 × upper normal limit) were included. The other inclusion criteria were age > 18 years, non-pregnant as confirmed by a negative urine pregnancy test, and absence of concomitant diabetes mellitus. Hepatitis B and C serologies were done and patients testing positive were excluded, as it could have a bearing on hepatotoxicity of study drugs which was one of the outcomes. Also, patients on anti-epileptic drugs, immunosuppressants and other drugs that induce liver microsomal enzyme systems were excluded. HIV infection was documented by licensed ELISA test kit (As per NACO guidelines). CD4/CD8 cell counts were determined by flow- cytometry (BD FACS CALIBUR). Viral load testing was done using AMPLICOR HIV-1 Monitor Test, version 1.5, manufactured by ROCHE Diagnostics. The protocol was approved by the institutional research Ethics Committee of the All India Institute of Medical Sciences, New Delhi. All participants gave signed informed consent to participate in this study.
This is the first study sponsored by National AIDS Control Organization, Ministry of Health & Family Welfare, Government of India from North India for estimation of plasma nevirapine concentrations in patients receiving nevirapine-containing HAART regimen along with rifampicin-based ATT. Its results indicate that good survival benefit is associated with concomitant administration of ATT and HAART. The mortality was slightly higher in the cases compared to controls. There are confounding factors like absence of tuberculosis in the control group that could be responsible for this difference in mortality. Overall good virological response was obtained in cases. The rate of immunological failure was statistically similar in both the groups. CD4 response (immunological response) is one of the determinants of the effect of HAART [17,18]. Good immunological response was achieved in both cases and control groups in our study. More than half of the patients had CD4 increase greater than 100 at 24 weeks post HAART. Study by Elisa Zaragosa-Macias, et al conducted at Atlanta, Georgia also reported 56% patients had CD4 increase greater than 100 from the baseline at 24 weeks post HAART .
The authors declare that they have no competing interests.
SS provided inputs to the study design, helped in data analysis and interpretation, wrote the manuscript, and did final editing. SD, NS, AB, KC, NB, RCS, ME and SKS reviewed literature, and helped in interpreting data and writing the manuscript. SK, TV and AKR conducted laboratory tests for nevirapine levels. HA, NK and JCS conducted laboratory tests for CD4 cell count and plasma viral load. VS did data analysis. RLM edited the manuscript. All authors approved and read the final manuscript.