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AIDS:
Research Letters

The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India

Kumarasamy, Nagalingeswarana; Solomon, Sunitia; Chaguturu, Sreekanth Kb; Mahajan, Anish Pb; Flanigan, Timothy Pb; Balakrishnan, Pa; Mayer, Kenneth Hb

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aYRG Centre for AIDS Research and Education, Chennai, India; and bMiriam Hospital, Brown Medical School, Providence, RI, USA.

Sponsorship: This work was supported by the AIDS International Research and Training Program of the Fogarty International Center of the National Institutes of Health, USA (grant no. 7D43TW00237) and Lifespan–Brown–Tufts Center for AIDS Research (grant no. 1P30AI42853).

Received: 7 March 2002; revised: 6 May 2003; accepted: 20 May 2003.

We investigated the safety, tolerability and effectiveness of locally produced generic highly active antiretroviral therapy (HAART) regimens with a chart review conducted at YRG CARE, a tertiary HIV referral centre in India. A total of 333 patients had been on Indian-manufactured generic HAART for at least 3 months. In this cohort, generic HAART was safe, well tolerated and effective at increasing CD4 T-lymphocyte counts in patients with advanced HIV, comparable to the experience with proprietary HAART.

Four million people are living with HIV in India [1]. Highly active antiretroviral therapy (HAART) has led to dramatic reductions in HIV-related morbidity and mortality in America and India [2,3]. The production of antiretroviral medications by generic manufacturers in developing countries has drastically reduced the price to below US$1 per day [4]. Lower prices have allowed centres in resource-limited settings to afford and administer HAART [2]. Because concerns have been raised that generic medicines may not be equivalent to proprietary therapeutic agents, we evaluated the safety, tolerability and effectiveness of generic HAART in a tertiary HIV centre in south India [5].

YRG CARE is a non-profit HIV referral centre in southern India providing care for nearly 5000 individuals living with HIV [2]. A chart review was conducted to identify patients who had been on Indian-manufactured generic HAART for at least 12 weeks from 1 May 2000 to 1 January 2003. CD4 lymphocyte counts were determined by flow cytometry (Becton Dickinson, New Jersey). Standard algorithms were used in the clinical management of prophylactic and therapeutic interventions. Individuals initiated antiretroviral therapy when asymptomatic and their CD4 lymphocyte count was less than 200 cells/μl or independently of their CD4 lymphocyte count if they had an AIDS-defining illness and were able to afford treatment [6].

The review included an assessment of documented opportunistic infections (OI) using established clinical criteria, CD4 cell counts, side-effects and adverse events [7]. The adverse events recorded included rash occurring within 6 weeks, hepatitis (elevated transaminases) within 12 weeks and anaemia, diarrhoea, headache, or nausea any time after initiating therapy. Study participants were seen every 3 months in addition to when they were symptomatic.

Statistical analyses were performed uisng SPSS software (version 10.07; SPSS, Chicago, IL, USA).

From 1 May 2000 until 1 January 2003, 333 patients (88% male, 95% acquired HIV heterosexually, median age 33 years) have been on generic HAART for at least 3 months, reflecting 279 person-years’ experience. At the initiation of HAART, the median CD4 cell count was 171 cells/mm3 (range 2–623 cells/mm3) and 54% of patients had active OI at HAART initiation (60% had pulmonary tuberculosis, 22% had extrapulmonary tuberculosis, 16% had cryptosporidial diarrhoea, 6% had toxoplasmosis, 6% had cryptococcal meningitis, and 5% had Pneumocystis carinii pneumonia). Patients began on generic HAART containing nevirapine in combination with zidovudine/lamivudine, stavudine/lamivudine or stavudine/didanosine. Sixty-eight patients (20%) had been on previous proprietary antiretroviral therapy. Of these, 55 patients had been on dual nucleoside reverse transcriptase inhibitor (NRTI) therapy and 13 had been on HAART containing a proprietary protease inhibitor or non-nucleoside reverse transcriptase inhibitor (Table 1).

Table 1
Table 1
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As a result of the high cost per CD4 cell count test, only 109 patients had a follow-up CD4 cell count within the first 6 months of HAART. The median increase in CD4 cell count from baseline for this group was 173 cells/mm3 (P = 0.001). Only 75 patients had a follow-up CD4 cell count between 6 to 12 months of initiating HAART. The median increase in CD4 cell count from baseline in this group was 192 cells/mm3 (P = 0.001). The median increase in CD4 cell count from baseline was greater in patients who were antiretroviral naive than in patients who had had previous dual nucleoside therapy (P = 0.01).

Twenty-six per cent of patients developed side-effects of anaemia, diarrhoea, peripheral neuropathy, hepatitis or rash attributed to the HAART regimens (Table 1). Table 1 compares the prevalence of nevirapine-associated rash among patients at YRG CARE with patients enrolled in clinical trials of comparable regimens manufactured by multinational pharmaceutical companies, and demonstrates comparable clinical profiles [8]. Fifty-three patients (16%) discontinued HAART, 34 (10%) as a result of side-effects. No patient died as a result of side-effects.

Thirty-three patients developed OI while on HAART, with a median time to development of 100 days (range 4–430). In a univariate analysis, patients who started generic HAART below a CD4 cell count of 100 cells/mm3 were more likely to develop an OI (P = 0.001) while on HAART.

There was an initial increase in CD4 cell counts, which subsequently leveled off after the initiation of generic HAART, similar to previous studies [9]. However, these data are limited by those who discontinued HAART and the few individuals who could afford repeated CD4 cell counts, viral loads and resistance testing.

Fifty-five patients had been on dual NRTI therapy before initiating HAART. These patients either initiated dual NRTI therapy before the introduction of HAART or had been started by physicians based outside YRG CARE. Antiretroviral-naive patients had a statistically significantly greater gain in CD4 cell counts than patients who had previously been on dual NRTI therapy. This may be explained by the development of resistance in dual NRTI regimens, but few patients were able to afford testing to verify this hypothesis.

The 33 patients who developed OI while on HAART were more likely to have initiated therapy at CD4 cell counts of less than 100 cells/mm3. Patients may be initiating HAART later than recommended because the prices are still prohibitively high for many. Patients in resource-limited settings may also have fewer healthcare encounters, with fewer doctors specializing in HIV care, and are thus presenting to physicians at later stages of disease and increasing their risk of progression.

Twenty-six per cent or patients developed side-effects, similar to proprietary HAART regimens. Only 10% discontinued use because of side-effects. No patient died as a result of drug toxicity.

All patients were prescribed generic nevirapine-based regimens because of the lower cost of nevirapine compared with generic protease inhibitors. One per cent of subjects discontinued therapy because of financial expenses. This could be attributed to both the falling cost of antiretroviral drugs and the extensive financial counseling that patients receive before initiating therapy.

In this cohort, generic-based HAART was safe, well tolerated and effective at increasing CD4 T-lymphocyte counts in advanced patients. Increasing access to generic HAART could be an effective means of using limited resources to provide needed treatment in areas where the epidemic continues to expand rapidly. Unfortunately, many of the world's poor living with HIV are still unable to afford and access antiretroviral therapy despite substantially lower prices. Government and non-government sectors must work together to address these issues.

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References

1. Ministry of Health and Family Welfare. National AIDS Control Organization (NACO). Combating HIV/AIDS in India 2000–2001. New Delhi: NACO; 2001.

2. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in southern India. Clin Infect Dis 2003, 36:79–85.

3. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998, 338:853–860.

4. Angerer T, Wilson D, Ford N, Kasper T. Access and activism: the ethics of providing antiretroviral therapy in developing countries. AIDS 2001, 15 (Suppl. 5):S81–S90.

5. Taylor RB, Shakoor O, Behrens RH, Everard M, Low AS, Wangboonskul J et al. Pharmacopoeial quality of drugs supplied by Nigerian pharmacies. Lancet 2001, 257:1933–1936.

6. US Public Health Service. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Washington, DC: US Public Health Service; 4 February 2002.

7. Centers for Disease Control and Prevention. Guidelines for national human immunodeficiency virus case surveillance, including monitoring for human immunodeficiency virus infection and acquired immunodeficiency syndrome. MMWR 1999, 48 (RR-13):1–28.

8. Boehringer Ingelheim Pharmaceuticals’ Viramune prescribing information. (n.d.). Retrieved 27 December 2002, from website http://www.bidocs.com/renetnt:/Prescribing+Information/PIs/ Viramune/Viramune.pdf.

9. Lederman M, Valdez H. Immune restoration with antiretroviral therapies: implications for clinical management. JAMA 2000, 248:223–228.#m AcknowledgementsThe authors are grateful to all the clinical staff of the YRG Centre for Research and Education, Chennai, India, and of the Immunology Center at Miriam Hospital, Providence Rhode Island, USA, for their generous facilitation of the study. The authors would also like to th thank the AIDS International Research and Training Program of the Fogarty International Center of the National Institutes of Health, USA (grant no. 7D43TW00237) and the Lifespan–Brown–Tufts Center for AIDS Research (grant no. 1P30AI42853) for their financial support.

© 2003 Lippincott Williams & Wilkins, Inc.

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