JAIDS Journal of Acquired Immune Deficiency Syndromes:
Brief Report: Clinical Science
Safety and Antiretroviral Effectiveness of Concomitant Use of Rifampicin and Efavirenz for Antiretroviral-Naive Patients in India Who Are Coinfected With Tuberculosis and HIV-1
Patel, Atul MD*; Patel, Ketan MD*; Patel, Jagdish MD†; Shah, Nitesh MD‡; Patel, Bhupendra BSc, MT§; Rani, Shubha∥
From the *Chief Division of Infectious Disease, Sterling Hospital, Ahmedabad, India; †Adit Diagnostic Center, Ahmedabad, India; ‡Sterling Hospital, Ahmedabad, India; §Shashwat Diagnostic, B.V. Patel PERD Center, Ahmedabad, India; and ∥B.V. Patél PERD Center, Ahmedabad, India.
Received for publication October 25, 2003;
accepted June 4, 2004.
Presented in part at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10–14, 2003 (oral abstract 138).
Reprints: Atul Patel, Division of Infectious Disease, Sterling Hospital, Off Gurukul Road, Ahmedabad, India (e-mail: firstname.lastname@example.org).
Objective: To study the safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naïve patients in India who are coinfected with tuberculosis (TB) and HIV-1.
Design and Methods: The study was an observational longitudinal cohort investigation. HIV-1–infected patients with CD4 cell counts of ≤200/μL who attended the Infectious Disease Clinic of Sterling Hospital (Ahmedabad, India) from June 2001 to December 2002 were recruited for the study. Patients were divided in 2 groups: group A, patients with active TB (n = 126); and group B, patients without TB (n = 129). Group A patients were given efavirenz with 2 nucleoside reverse transcriptase inhibitors along with rifampicin-containing anti-TB treatment. Group B patients were treated for presenting opportunistic infections and started therapy with efavirenz plus 2 nucleoside reverse transcriptase inhibitors. The nucleoside reverse transcriptase inhibitors were either zidovudine and lamivudine (n = 30) or stavudine and lamivudine (n = 225). Patients self-funded their investigations and medications (antiretroviral, anti-TB, and other opportunistic infection–related agents). Indian generic medications were used.
Results: Efavirenz-based highly active antiretroviral therapy with rifampicin for HIV/TB-coinfected patients resulted in an immunologic response that was comparable with that of the group not receiving rifampicin. Median CD4 cell counts at baseline, 3 months, 6 months, and 9 months in group A were 84/μL (range, 5–200/μL), 225/μL (range, 26–528/μL), 251/μL (range, 65–775/μL), and 275/μL (range, 61–611/μL), respectively, and in group B, these values were 118/μL (range, 2–200/μL), 244/μL (range, 38–881/μL), 294/μL (range, 23–1322/μL), and 295/μL (range, 26–991/μL), respectively. The overall increase in CD4 cell count was greater in group A than in group B at 9 months (190 vs. 176/μL, respectively). Patients in both groups tolerated the therapy well; the adverse effects profile was comparable except that group A patients had a higher incidence of hepatitis than group B patients (13.49% vs. 0, respectively; P < 0.0001).
Conclusion: Clinical and immunologic benefits are comparable for patients receiving efavirenz-based antiretroviral therapy with or without rifampicin.
Tuberculosis (TB) remains one of the most important infections in HIV-infected individuals. Twenty-three percent of the total global TB incidence each year is among 1 billion people in India.1 The incidence of TB as a presenting illness in HIV-infected patients is high, and TB is also a common cause of death in these patients. A decreased risk of death has been observed in patients starting highly active antiretroviral therapy (HAART) compared with those not receiving HAART after the diagnosis of TB.2–4 In India, there are now effective treatments available for both HIV infection and TB. Concomitant administration of HAART and anti-TB medications is often difficult because of drug–drug interactions and the adverse effects profile.5–8 Many of the adverse effects are thought to be due to the use of rifampicin with various antiretroviral drugs (protease inhibitors and nonnucleoside reverse transcriptase inhibitors). There is documented evidence of increased mortality, relapse, and treatment failure for HIV-infected persons who receive non–rifampicin-containing continuation phase treatment of TB compared with those who receive rifampicin-based treatment. Rifampicin is a potent inducer of the CYP3A system. It lowers the concentration of saquinavir, lopinavir, nelfinavir, indinavir, amprenavir, and delavirdine in serum by 75%–95%.9–15 Rifampicin decreases efavirenz levels by >20%, which is more marked in individuals with higher body weight.16 Low trough levels of these drugs are potentially associated with incomplete viral suppression and emergence of drug resistance. Rifampicin can be used in combination with ritonavir or efavirenz. However, little data on the clinical and immunologic implications of combination therapy with rifampicin and efavirenz for HIV-1–infected persons are currently available. The optimum time to consider HAART for such individuals is not yet known.
We describe our clinical experience with treating TB/HIV-coinfected patients who were prescribed a rifampicin-containing anti-TB regimen and efavirenz-based HAART regimen and their associated immunologic recovery (CD4 cell counts).
An observational cohort study was conducted at a tertiary HIV referral center in Ahmedabad, India. HIV-seropositive patients who presented from June 2001 to December 2002 were evaluated. Patients self-funded their treatment and laboratory investigations. Patients with CD4 cell counts of ≤200/μL (n = 255) started efavirenz (600 mg)–based HAART (2 nucleoside reverse transcriptase inhibitors and efavirenz). Baseline clinical and demographic data were collected. The nucleoside reverse transcriptase inhibitors used were either zidovudine and lamivudine (n = 30) or stavudine and lamivudine (n = 225) as selected by the treating physician. All antiretrovirals were Indian generic medications. Patients receiving HAART were divided in 2 groups: group A, patients with active TB (n = 126); and group B, patients without TB (n = 129).
Definite TB was defined as a clinical illness consistent with TB accompanied by a sputum smear positive for acid-fast bacilli or typical histopathologic findings in a surgical specimen. Probable TB was defined either as a clinical illness with ultrasonographic abdominal examination showing enlarged lymph nodes with splenic infiltration or as matted peripheral lymphadenopathy with clinical response to standard anti-TB treatment. Many patients were diagnosed with TB using clinical and radiologic parameters.
Anti-TB treatment was the combination of isoniazid (5 mg/kg), rifampicin (10 mg/kg), ethambutol (20 mg/kg), and pyrazinamide (25 mg/kg) along with HAART. Streptomycin (15 mg/kg) was added to the standard 4-drug regimen in cases with disseminated disease (n = 37) and in retreatment cases (n = 9). Pyrazinamide, ethambutol, and streptomycin were discontinued after the first 3 months, whereas isoniazid and rifampicin were continued for a total 9 months. Patients with intracranial TB (TB meningitis and tuberculomas), TB involving ≥2 organs, miliary TB, and a history of TB (n = 46) were given anti-TB treatment for an extended period. Drug-induced hepatitis was defined as a symptomatic elevation in the alanine aminotransferase level of any degree or an asymptomatic elevation in the alanine aminotransferase level of >100 IU/L (upper limit of normal, 40 IU/L). Patients who developed hepatitis were treated with discontinuation of hepatotoxic anti-TB drugs (isoniazid, rifampicin, and pyrazinamide) while continuing streptomycin and ethambutol as well as HAART (2 nucleoside reverse transcriptase inhibitors and efavirenz). Once liver enzyme levels normalized, rifampicin was introduced first followed by isoniazid and finally pyrazinamide. Co-trimoxazole (1 trimethoprim–sulfamethoxazole double-strength tablet once daily) prophylaxis was given to all patients. Patients underwent monthly follow-up with clinical examination. Those patients with a positive sputum smear were examined on a monthly basis for acid-fast bacilli until sputum conversion. Liver profile and renal function tests were carried out as directed by symptoms and signs during clinical assessment. Repeated ultrasonography was performed for patients with abdominal lymph nodes at 3 months. CD4 cell count analyses were done every 3 months for all patients. Patients in group A started HAART and anti-TB treatment concomitantly. Adherence to HAART was assessed by self-reporting. Plasma viral load testing and therapeutic drug monitoring were not done.
The analytical end point of the study was the absolute CD4 cell count at 9 months. To assess the change in CD4 cell counts from baseline values between patients with and without TB, nonparametric Wilcoxon 2-sample testing was performed at each time point. The analysis of adverse events compared the groups by the paired χ2 test.
Both groups were age and sex matched as shown in Table 1. A total of 126 patients received anti-TB treatment, of whom 51 (40.47%), 38 (30.15%), and 37 (29.36%) had extrapulmonary TB, pulmonary TB, and pulmonary with extrapulmonary TB, respectively. All patients completed 9 months of anti-TB treatment and HAART; 86 patients were declared cured of TB at the end of 9 months of therapy and assessment. Forty patients required extended anti-TB treatment for the reasons cited above. None of the patients died during follow-up. Paradoxical worsening, defined as transient worsening or exacerbation of symptoms and lesions during therapy that was documented by clinical examination and radiologic investigations, was observed in 11 group A patients and 3 group B patients.
Baseline CD4 cell counts were significantly lower in patients with TB (median CD4 cell count: 84/μL in group A vs. 118/μL in group B, respectively) (P = 0.0004). Median CD4 cell counts increased in response to HAART in both groups as shown in Table 2. Increases in median CD4 cell counts in both groups at different time points are shown in Figure 1.
HAART has changed the natural history, response to therapy, and outcome of opportunistic infections and TB in HIV-infected patients. A decreased risk of death related to TB was observed in patients receiving HAART.2,17–20 However, treatment of TB/HIV coinfection is difficult because of drug–drug interactions between rifampicin with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, which are important constituents of HAART. Efavirenz-based HAART is now preferred due to its efficacy and better tolerance. There is a concern of decreased bioavailability of efavirenz in combinations with rifampicin,16 but sufficient data on its clinical implications are not available.
This observational study showed that for patients with TB/HIV coinfection the concomitant use of rifampicin with efavirenz did not change the response to HAART and was safe and tolerated well. Increases in CD4 cell counts were comparable for both groups and, in fact, were better for the group of patients with TB. This finding may be due to suppressed CD4 cell counts with active TB infection, which improved with anti-TB treatment and HAART. Hung et al21 also showed a similar observation.
Despite the pill burden and overlapping toxicities between anti-TB treatment and HAART, the adverse effects profile was comparable in this study, except for hepatitis in patients receiving anti-TB medications (Table 3): 13.49% patients in this group developed hepatitis compared with none of those without anti-TB treatment (P < 0.0001). The conditions of all patients who developed hepatitis improved within 1 month of discontinuation of hepatotoxic anti-TB drugs (isoniazid, rifampicin, and pyrazinamide) and continuation of streptomycin and ethambutol. Anti-TB drugs were reintroduced in a stepwise manner once liver enzyme levels normalized. The incidence of peripheral neuropathy was not significantly increased despite more patients receiving stavudine and isoniazid (5.55% for group A vs. 3.1% for group B; P = 0.5116). Breen et al20 reported an increased incidence of peripheral neuropathy (55%) for HIV-infected patients prescribed isoniazid and stavudine concomitantly.22
Most patients took their medications regularly with few treatment interruptions, which lasted for 1 or 2 days per month. This usually happened before their scheduled visits. Paradoxical worsening was seen more in patients with TB than in those without TB (11 [8.73%] vs. 3 [2.32%], respectively; P = 0.0489). This finding may possibly be related to more suppressed CD4 cell counts, which subsequently improved rapidly with therapy for the group of patients with TB. The proportion of patients with paradoxical worsening in this study is similar to that previously reported.23,24 Narita et al25 showed that 36% of their patients developed paradoxical worsening when anti-TB and antiretroviral treatments were initiated. In these studies, the mean time to the onset of paradoxical worsening was 15 days after the initiation of antiretroviral therapy. In our cohort, all but 1 patient developed paradoxical worsening within 1 month after initiation of therapy.
In conclusion, our observational study done at a clinical practice showed that concomitant use of efavirenz and rifampicin resulted in no measurable increase in immunologic failure as defined by CD4 cell counts and no increase in failure to cure TB at the end of a 9-month course of treatment. Adverse effects appeared to be most attributable to the anti-TB medications and could be managed with discontinuation and subsequent judicious reintroduction of the offending drugs.
The authors thank Drs. Janak Patel, Chirag Vasa, Nilay Mehta, and S. Dileep (Ahmedabad, India) for their invaluable help with preparation of the manuscript.
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