Adverse effects after HAART Initiation in resource-limited settings : a prospective study from Mysore , India

Introduction: There are few studies from India documenting the adverse effects of generic HAART (Highly Active Anti-retroviral Therapy). Methodology: A prospective study was conducted at Mysore, India, to study the adverse effects after HAART initiation in a cohort of 100 antiretroviral therapy (ART)-naive patients, who were evaluated prospectively every three months by clinical and laboratory monitoring for adverse effects after HAART initiation for one year. Results: The most common first-line regimens were zidovudine (AZT) plus lamivudine (3TC) plus nevirapine (NVP) (42%); followed by Stavudine (d4T) plus 3TC plus NVP (33%); AZT plus 3TC plus efavirenz (EFV) (13%); and d4T plus 3TC plus EFV (12%). The first-line regimen was modified in14% of patients. The most common reasons for modifying therapy were development of an adverse effect (eight cases; 57.14%) and completion of antituberculous therapy (six cases; 42.86%). The commonest cause for modifying therapy was skin rashes due to NVP (four cases) followed by anaemia two cases) and peripheral neuropathy (two cases). Grade 1 or 2 severity adverse effects by laboratory monitoring were seen in 54 patients after ART initiation and grade 3 or 4 severity adverse effects were seen in eight patients. Conclusions: A significant proportion of patients had adverse effects of a lower grade severity after HAART. A significant proportion of those started on ART substitute therapy due to adverse effects and those on NVP-based regimens are more likely to do so when compared with those on non-NVPbased regimens.


Introduction
The World Health Organization (WHO) declared the lack of access to antiretroviral therapy (ART) a "global health emergency" in 2003, and announced an emergency plan to scale up access to ART for at least three million people by 2005 [1].The cost of highly active antiretroviral therapy (HAART) has been brought down by various international initiatives [2].In India, the National AIDS Control Organization (NACO) introduced inexpensive and generic ART drugs [3].So, with the availability of generic HAART at low cost, an increasing number of HIV-infected individuals in India are now receiving therapy [4].Many studies in developing countries have demonstrated the safety, tolerability, and efficacy of generic HAART [5,6].However, few studies from India document the adverse effects of these drugs.This prospective study was therefore conducted at Mysore, India, to determine the adverse effects after HAART initiation in a cohort of 100 patients.

Study design and setting
A prospective-observational cohort study involving 100 HIV-positive ART-naïve patients was conducted at the ART Centre, Krishna Rajendra Hospital, Mysore Medical College and Research Institute, Mysore, India.Duration of the study period was one year from 20 August 2006 to 19 August 2007.This study was approved by the ethics committee of our institution.
These HIV-positive individuals first underwent pre-ART counselling and were registered at the ART centre of our hospital.After clinical evaluation, informed consent was taken from these patients.They were enrolled into the study if they were found eligible for ART per the NACO guidelines and fulfilled the following inclusion criteria.

Inclusion criteria
HIV infected adults, above 18 years of age from both sexes, who satisfied the following criteria were included in the study:

Exclusion criteria
Patients who had symptoms of pancreatitis or peripheral neuropathy were excluded.
All included patients were initiated on various HAART regimens by strictly following the NACO guidelines [8].After HAART initiation, these patients were followed up at regular intervals every three months.At each follow-up visit, complete blood count, liver function tests (serum bilirubin, AST and ALT), and serum creatinine were performed.This routine was continued up to the end of the study period.The adverse clinical events and the abnormal laboratory findings were documented.

Statistics
Descriptive statistics such as percentages and medians were calculated wherever appropriate.Comparison of NVP-based and non-NVP-based regimens was done using chi-square/Fischer's exact test and P-value was calculated.All P-values ≤ 0.05 were considered significant.All statistical analyses were performed using SPSS software (version 16.0, SPSS, Chicago, USA).
The most common reasons for modifying therapy were development of an adverse effect (eight cases; 57.14%) and completion of antituberculous therapy (six cases; 42.86%), which necessitated the change of regimen from efavirenz to nevirapine per the NACO guidelines, with median times to modify therapy being 76 days for the former and 138 days for the latter, respectively.
In those subjects with adverse effects, the commonest cause for modifying therapy was skin rashes due to NVP (four cases) followed by anaemia (two cases) and peripheral neuropathy (two cases).One patient discontinued therapy entirely primarily due to nevirapine sensitivity after a median duration of 38 days.The adverse events of various grades of severity are given in Tables 1a and 1b.
The severity of laboratory toxicities was assessed based on the WHO criteria [7].Grade 1 or 2 severity adverse effects by laboratory monitoring were seen in 54 patients after ART initiation and grade 3 or 4 severity adverse effects were seen in 8 patients.This observation shows that the majority of patients have adverse effects after ART initiation, but of a lower grade severity.
A total of nine cases showed low haemoglobin levels during follow-up.Of these, three were of grade 4 severity (Hb < 6.5g/dL), one of grade 2 severity (7.0-7.9g/dL) and five of grade 1 severity (8.0-9.4g/dL)during the first follow-up at three months.However, these numbers dropped to six cases during the second follow-up, at which time four cases suffered adverse effects of grade 1 severity and two with adverse effects of grade 2 severity.During the third follow-up, two cases showed haemoglobin levels of grade 2 severity; however, there was no statistically significant association with zidovudinebased regimens.This result could possibly be due to the short duration of the study period as well as the improvement in the haemoglobin levels following HAART initiation.
Table 2 shows the comparison of patients who modified their first-line regimens based on whether they were on NVP-based or non-NVP-based regimens.Note: These parameters are strictly per the WHO guidelines [8] .

Table 1a .
Adverse events of grade 1 or 2 severity by laboratory monitoring

Table 1b .
Adverse events of grade 3 or 4 severity by laboratory monitoring