Indian Journal of Medical Sciences Medknow Publications on behalf of Indian Journal of Medical Sciences Trust ISSN: 0019-5359 EISSN: 1998-3654 Vol. 61, Num. 7, 2007, pp. 390-397

Indian Journal of Medical Sciences, Vol. 61, No. 7, July, 2007, pp. 390-397

Original Contributions

Antiretroviral treatment in resource-poor settings: A view from India

Vajpayee Madhu, Kaushik Shweta, Mojumdar Kamalika, Sreenivas V

Department of Microbiology, All India Institute of Medical Sciences (A.I.I.M.S.), New Delhi
Correspondence Address:HIV and Immunology Division, Department of Microbiology, All India Institute of Medical Sciences (A.I.I.M.S.), Ansari Nagar, New Delhi - 110 029 mvajpayee@hotmail.com

Code Number: ms07065

Abstract

Keywords: Antiretroviral therapy, human immunodeficiency virus-1, India, resource-poor

The devastating social and economic impact of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has led to the launch of HIV-prevention campaigns emphasizing the administration of powerful antiretroviral drugs. However, the guidelines to monitor antiretroviral therapy in the developed world rely heavily on laboratory tests based on advanced technologies that may not be feasible or available in resource-poor settings. ^[1] Hence it is imperative to identify and design monitoring strategies using the available technologies in resource-limited settings with a conceptual framework that takes into account the differences between rich and poor countries and provide the greatest benefit to HIV-infected people in the developing world. ^{[2],[3],[4],[5],[6],[7],[8]}

Materials and Methods

The present study was a longitudinal cohort study conducted at the AIDS clinic of a tertiary care hospital. The study population of 166 HIV-infected individuals was referred to the AIDS clinic from the outpatient clinics of different departments in the hospital. All the 166 study subjects had at least two follow-ups after initial visit, at approximately 6-8 months′interval during the period January 2002 to November 2006. The appropriate institutional ethics committee approved the study, and all the patients gave written and informed consent prior to entering the study.

The HIV antibody status of all the study subjects was assessed by three ERS [enzyme-linked immunosorbent assay (ELISA), rapid, simple] as recommended by the National AIDS Control Organization (NACO), Ministry of Health and Family Welfare, Government of India. ^[9] All the tests were performed according to the manufacturer′s recommendations. First and second-line antiretroviral-therapy regimen consisted of highly active antiretroviral therapy (HAART) or dual therapy of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), following WHO guidelines, as recommended by the Indian government. The diagnosis of pulmonary TB was based on consistent history and physical examination, positive sputum test for acid-fast bacilli and radiologic features compatible with TB. ^[10] Extrapulmonary tuberculosis, but not pulmonary tuberculosis, was considered an AIDS-defining illness. ^[11] The tuberculosis regimen consisted of 2 months of isoniazid, rifampicin ethambutol and pyrazinamide daily, followed by 4 months of isoniazid and rifampin daily. ^[12]

The CD4+ T-cell percentages and counts of all 166 HIV-infected individuals were enumerated at each visit of the patient by dual-color immunophenotyping using standard whole-blood methodology, four-tube panel: CD45 /CD14; CD3 /CD4; CD3 /CD8 and isotype controls Igg1/Igγ1. ^[13],[14] The specimens were acquired and analyzed by the CELLQuest software on identically configured FACS Calibur flow cytometer (Becton Dickinson, San Jose, USA).

The mean and median of all study variables were computed for all the patients at each visit. The changes in the median CD4 counts at follow-up visits were observed in different treatment groups using a repeated-measures ANOVA technique. SPSS version 11.5 and STATA 8.0 software were used for all statistical analysis.

Results

Patients′profile

Of the 166 HIV-infected patients comprising the study population, 95 (57%) had not previously received antiretroviral therapy, and therapy was initiated in these patients at their subsequent follow-up visits; 37 (22%) had early-stage HIV disease and did not require antiretroviral therapy; 34 (20%) had been receiving antiretroviral therapy before enrollment in the study. The baseline characteristics of the study population have been summarized in [Table - 1]. All the 166 patients had at least three visits to the laboratory, with the initial being the baseline visit and subsequent two follow-up visits by November 2006. [Table - 2] details the distribution of the entire study population according to the duration of their follow-up visits. The most frequent mode of transmission was found to be heterosexual contact - 67 (40.3%) among the study participants [Figure - 1].

Out of 132 study subjects that were initiated treatment during follow-up visits or did not require treatment, 111 patients were only HIV infected (HIV+TB-), and 31 patients were dually infected with HIV and TB (HIV+TB+). The distribution of the study population in different disease and treatment groups has been detailed in [Table - 3].

CD4 ⁺ T-cell profile

The 109 males (66%) in the study group of 166 HIV-seropositive individuals had the baseline mean CD4 count of 271 cells/µl (range: 16 to 1,244) as compared to 308 cells/µl (range: 28 to 880) among 57 (34%) females. The baseline mean CD4 counts of the study population in different subgroups are presented in [Table - 1].

[Table - 4] shows the median CD4 counts of 95 study subjects followed up for different time intervals even before the initiation of therapy. The median CD4 counts at the last visit before the start of antiretroviral therapy, considered as the baseline median CD4 counts, were < 200 cells/µl in all the groups of patients according to their follow-up time intervals. The median CD4 counts were also calculated at different follow-up time intervals for 37 HIV-infected individuals who did not require antiretroviral therapy [Table - 5]. These patients maintained CD4 counts above 200 cells/µl at all time intervals for which they were followed up, thus requiring no treatment.

Changes in CD4 ⁺ T-cell counts: We observed an increased median CD4 T-cell count (256 cells/µl, range: 177 to 374) at the first visit after initiation of antiretroviral treatment as compared to the median baseline value (179 cells/µl, range: 126 to 266) in 95 HIV-infected individuals who received treatment at the follow-up visits [Table - 6]. This trend of increasing median CD4 counts was observed at all subsequent follow-up visits after initiation of antiretroviral treatment as compared to the median baseline value. However, the increase in median CD4 counts after the initiation of therapy was more apparent in the first visit (change 1) as compared to the increase observed at subsequent follow-up visits [Figure - 2]. The first increase (change 1) in the median CD4 counts was calculated by subtracting the baseline CD4 count value from the CD4 count value at the first visit after initiation of antiretroviral treatment. Similarly, the second increase (change 2) was obtained by subtracting the CD4 count value at the first visit after initiation of antiretroviral treatment from the median CD4 count value at the second follow-up visit after therapy; and similarly, calculations were done for changes at subsequent visits. The results also indicate that the median CD4 counts increase sharply within the first follow-up visit after the administration of antiretroviral therapy and subsequently this increase is not quantitatively significant [Figure - 2].

Effect of treatment on CD4 counts: The repeated-measures analysis of variance was performed for 132 study subjects that were initiated treatment during follow-up visits or did not require treatment and had at least 2 follow-up visits [Figure - 3]. The results indicated trends for the increase in median CD4+ T-cell counts at subsequent follow-up visits in both the groups of HIV+TB+ of 5 individuals and HIV+TB- of 80 individuals receiving only antiretroviral treatment. The group of 10 HIV+TB+ patients receiving dual therapy (ART+ATT) Anti Tuberculosis Therapy (ATT) also showed marked improvement in median CD4 counts at follow-up visits. The HIV+TB+ group of 5 individuals receiving treatment only for tuberculosis (ATT) had slight improvement in CD4 counts. The HIV-seropositive individuals with no tuberculosis infection maintained CD4 counts in absence of any treatment.

Discussion

The introduction of highly effective antiretroviral drugs at affordable costs has greatly transformed the AIDS epidemic in the resource-poor developing world. However, the effective delivery of antiretroviral therapy to combat this AIDS epidemic by implementation of free public sector ART program requires formulation of guidelines for the appropriate monitoring of treatment effectiveness and adherence to therapy using low-cost and simple clinical and laboratory measures that are available in the resource-poor settings. ^{[15],[16],[17],[18]} The limited data available to develop such guidelines in resource-poor settings led us to analyze the efficacy of antiretroviral treatment, adherence to therapy and motivation of patients for regular treatment monitoring by CD4 counts in the already established cohort of 166 HIV-1-infected Indian individuals at the All India Institute of Medical Sciences, New Delhi.

A significant number of individuals [95 (57%)] within the study population had not previously received antiretroviral therapy, and it was initiated in these patients at their subsequent follow-up visits. Thirty-four (20%) patients had already been receiving antiretroviral therapy before their enrollment in the study. These observations emphasize that the prospects for antiretroviral therapy in developing countries have changed recently with the availability of cost-effective generic drugs. ^[19],[20] The regular follow-up visits by these patients receiving antiretroviral treatment and 37 patients who had early-stage HIV disease but did not require antiretroviral therapy not only indicate the antiretroviral treatment adherence but also suggest the growing awareness and motivation for regular HIV disease monitoring in patients in the developing countries.

The WHO has proposed public-health approach to antiretroviral therapy (ART) to enable scaling up of access to treatment for HIV-positive people in developing countries, recognizing that the Western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-poor settings. ^[21] In an attempt to replicate resource-rich CD4 count guidelines for treatment decisions and monitoring in resource-poor settings of developing countries like India, we studied the CD4 outcome in our study population. In 95 out of 166 HIV-infected individuals forming the study population, we observed a trend of increasing median CD4 counts at all subsequent follow-up visits after initiation of antiretroviral treatment as compared to the baseline median CD4 count value, with the increase in median CD4 counts being more apparent in the first visit (change 1) as compared to the increase observed at subsequent follow-up visits [Figure - 2]. These observations underscore the importance of CD4 counts in monitoring of antiretroviral treatment effectiveness even in resource-poor settings and in the presence of other problem background infections, thus guiding future efforts for the development of widely available, low-cost methods for measuring CD4 counts.

We observed trends for increase in median CD4+ T-cell counts at subsequent follow-up visits in both the groups of HIV+TB+ and HIV+TB- patients receiving only antiretroviral treatment [Figure - 3]. These results underscore the potential benefits of antiretroviral therapy in HIV-infected individuals and emphasize the importance of ART regimens in resolving CD4 lymphopenia in persistent opportunistic infections like TB in HIV+TB+ patients. The HIV+TB+ group of 31 individuals receiving only treatment for tuberculosis (ATT) had slight improvement in CD4 counts. Hence the treatment of opportunistic infections like TB may not only slow the progression of HIV disease in patients dually infected with HIV and TB but may also be beneficial for patients facing a high risk of imminent death due to TB in developing countries like India. ^{[22],[23],[24],[25],[26],[27],[28]} These results also indicate the benefits of tuberculosis treatment for HIV management in the absence of availability of antiretroviral treatment in resource-poor settings. However, the group of HIV+TB+ patients (n = 10) receiving dual therapy (ART+ATT) showed better improvement in median CD4 counts at follow-up visits, suggesting that a combined ART and ATT therapy regimen may be a better treatment modality to follow in such dually infected patients. Thus the initiation of effective antiretroviral treatment focused on clinical symptoms may also form a basis for new program-based strategies with the goal of population-wide reduction in morbidity and mortality in developing countries.

Hence, even in the absence of standard laboratory monitoring facilities available in industrialized settings, the study outcome presents an optimistic future outlook by addressing key issues of concern for the development of antiretroviral treatment program with less intense monitoring that has the potential to reduce morbidity and mortality from HIV in the high-prevalence and high-′case load′developing countries like India. Future research with larger study group and long-term follow-up of patients may further assist the efforts of establishing cohorts as emphasized by the study outcome. This may be possible with free availability of antiretroviral drugs. This will also give us insight into the pathogenesis of HIV in infected Indian patients.

References

Copyright 2007 - Indian Journal of Medical Sciences

The following images related to this document are available:

Photo images