To the Editor:
The World Health Organization recommends the use of generic nevirapine (NVP)/efavirenz (EFV)-based highly active antiretroviral therapy (HAART) regimens as first-line therapy in the management of HIV in resource-limited settings.1 Initiating NVP-based HAART at elevated CD4 cell counts can lead to liver toxicity.2,3 Short-term risk of liver toxicity has been reported in men with CD4 counts greater than 400 cells/μL and in women with CD4 counts greater than 250 cells/μL. Hence, clinicians are advised to monitor the results of liver chemistry tests closely in the first 18 weeks of therapy because of the potential to develop life-threatening hepatic events.4 Mocroft et al5 showed that initiating NVP therapy at elevated CD4 levels may be safe for use in antiretroviral-experienced patients. Little is known about short-term adverse consequences and clinical outcome at elevated CD4 cell counts in a resource-limited setting.
We aimed to determine whether switching to NVP-based HAART is safe, tolerable, and effective for HIV-infected men and women at elevated CD4 cell counts after immune reconstitution with EFV-based HAART at a tertiary HIV referral center in southern India. This was a prospective study conducted at the YRG Center for AIDS Research and Education (CARE), a nonprofit HIV referral center in southern India providing care to more than 10,000 HIV-infected individuals. All patients are treated according to World Health Organization treatment guidelines. Patients are advised to initiate antiretroviral therapy before their CD4 counts are <200 cells/μL or when their CD4 counts range between 200 and 350 cells/μL with an AIDS-defining illness and if they can afford treatment. NVP-based regimens, which are the least expensive and most widely available, are generally used as first-line therapies. Data were collected under the approval of YRG CARE's free-standing Institutional Review Board.
Treatment outcomes were analyzed in a homogeneous treatment-experienced cohort of participants from a prospective clinical trial who had been initiated on prior EFV combination HAART. Patients had CD4 levels and liver function assessed quarterly. Patients were monitored for the development of hepatic-related toxicities and clinical failure for 12 months after switching from an EFV-based to NVP-based treatment regimen. Standard laboratory testing included a complete blood cell count, serum chemistry, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, total bilirubin (TBR) level, and CD4 cell count. Changes in serum ALT, AST, and TBR levels were categorized by means of a standardized toxicity grade scale (modified from that used by the AIDS Clinical Trials Group6). All statistical analyses were performed using SPSS software (version 13.0; SPSS, Chicago, IL).
Forty participants were initially enrolled in a prospective clinical trial on EFV-based HAART for a 2-year trial. After the end of the trial, 36 participants were enrolled in the Global Fund for AIDS, TB and Malaria (GFATM) antiretroviral therapy roll-out support program with NVP-containing HAART as part of posttrial access. Forty-two percent of participants were female, and the median age was 33.8 ± 7.4 years.
As Table 1 shows, at the time of initiating EFV-based HAART, the median CD4 cell count was 162 cells/μL (interquartile range [IQR]: 110 to 237 cells/μL). At the time of the switch to NVP-based HAART, the median CD4 cell count had risen to 463 cells/μL (IQR: 320 to 568 cells/μL). By the end of the 12-month follow-up period, the median CD4 count was 562 cells/μL (IQR: 405 to 712 cells/μL). Four participants were lost to follow-up, and 4 participants did not fully complete the 12-month follow-up because of a late switch date.
Liver enzymes did not significantly change from the time of initiating EFV therapy to substitution with NVP therapy and the end of the 12-month follow-up period. The number of patients presenting with elevated liver enzyme levels decreased during the 12-month follow-up period. At the time of initiating EFV therapy, 2 patients had grade 0, 5 patients had grade 1, and 1 patient had grade 2. At the time of the switch to NVP therapy, 4 patients had grade 1; at 3 months, 2 patients had grade 1; at 9 months, 2 patients had grade 1; and at 12 months, 1 patient had grade 1 and 1 patient had grade 2.
These data suggest that patients whose systems are immune reconstituted when switched to NVP-based HAART at elevated CD4 levels do not present with increased liver enzyme levels. This study suggests that NVP-based HAART at increased CD4 levels in these patients is effective, safe, and well-tolerated, while increasing CD4 T-lymphocyte counts. The number of HIV-infected patients who are newly placed on NVP therapy continues to increase globally. Greater understanding of the pathogenesis of NVP toxicity allows for improved clinical treatment guidelines.
Tuberculosis (TB) is one of the most common opportunistic infections in developing countries, and many of these patients require HAART. EFV-based HAART is recommended, along with rifampicin-based anti-TB therapy.1 Based on these results, TB-infected patients on EFV-based HAART can be safely switched to NVP-based HAART after TB therapy is completed, even if they have undergone immune reconstitution.
Combinations with EFV are almost twice as expensive as NVP combinations, which cost between $20 and $25 per month. Low-cost approaches, such as NVP-based therapy, must be assessed for their use in a range of patients with differing clinical, immunologic, and viral profiles. Additionally, clinicians need accurate information regarding the risk of hepatotoxicity and clinical failure associated with short-term and long-term NVP at high CD4 levels, especially in developing world settings, where an increasingly large number of HIV-infected men and women are on generic NVP-based treatment regimens.
The authors are grateful to the research nurses and all the clinical staff at the YRG CARE, VHS, Chennai, India, for their facilitation of the study. The authors thank Brown University's AIDS International Research and Training Program of the Fogarty International Center at the US National Institutes of Health (NIH; grant D43TW00237) and the AIDS Clinical Trials Group-International Clinical Trial Unit/NIH-Chennai site grant for supporting this study.
N. Kumarasamy, MBBS, PhD*
Kartik K. Venkatesh, BA†
Bella Devaleenal, MBBS, DLO*
Vidhya Palanivel, BDS*
Anitha J. Cecelia, MSc*
Sundaram Muthu, MSc*
Tokugha Yepthomi, MBBS, DO*
Kenneth H. Mayer, MD‡
Timothy Flanigan, MD‡
*YRG Center for AIDS Research and Education Voluntary Health Services Chennai, India
†Brown Medical School Providence, RI
‡Miriam Hospital/Brown Medical School Providence, RI
1. World Health Organization. Scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach-2003 revision. Available at: http://www.who.int/hiv/pub/prev_care/en/arvrevision
2003en.pdf. Accessed December 30, 2006.
2. Puro V, Soldani F, De Carli G, et al. Drug-induced aminotransferase alterations during antiretroviral HIV post-exposure prophylaxis. AIDS
3. Ena J, Amador C, Benito C, et al. Risk and determinants of developing severe liver toxicity during therapy with nevirapine- and efavirenz-containing regimens in HIV-infected patients. Int J STD AIDS
5. Mocroft A, Lacombe K, Rockstroh J, et al. Risk of discontinuation of nevirapine due to toxicities in antiretroviral naive and experienced patients with high and low CD4 counts. Presented at: XVI International AIDS Conference; Toronto; 2006.
6. AIDS Clinical Trials Group. Table for Grading the Severity of Adult Adverse Experiences
. Rockville, MD: National Institutes of Health, Division of AIDS; 2004.