Prevalence of virological failure amongst WHO- defined immunological failure HIV patients on first line of highly active antiretroviral therapy in a tertiary care hospital in Haryana, India

INTRODUCTION

The primary goals of initiating highly active antiretroviral therapy (HAART) among HIV patients are to suppress HIV viral replication and to restore immune function. As the global experience has increased over last few years, there have been changes in timing of initiation of ART, which regimen to follow and monitoring mechanisms. The clinical decision to check whether such goals have been achieved is made through CD4 cell counting.¹

Virological monitoring, though being the most sensitive tool, is not done routinely because of its high cost, advanced technological infrastructure requirement and limited access in most resource limited settings.^2,3 Therefore CD4 cell count becomes a crucial element in monitoring treatment response.

Due to the lack of routine pVL monitoring for HAART, the patient is designated as having treatment failure only after 6 – 12 months of failure of CD4 reconstitution, and is continued with the same ARVs with further delay in switching over to second-line therapy.

It has been well established that virological failure precedes Immunological failure which precedes clinical failure.⁴

The initiation of HAART generally leads to a rapid reduction in HIV-RNA plasma levels and to an increase in peripheral CD4 count.^5,6 However, some patients experience a discordant response, whereby the HIV-RNA plasma level is below the limit of detection but the CD4 cell count response is blunted. There are limited data on discordant responses in patients being treated in India.⁷

Four scenarios are expected during the antiretroviral treatment for HIV (as shown in Table 1).

A detectable plasma viral load (pVL) is among the earliest signs of treatment failure and continuing a failing regimen has been associated with increased morbidity and mortality as well as accumulation of drug-resistance mutations that further limit second-line options.^8-10 Therefore, routine virological monitoring is the standard of care in developed world.¹¹ However, because of cost and limited access to laboratory technology, routine pVL monitoring is not performed or recommended in resource-limited settings.¹² Instead, clinicians in these settings rely on defining treatment failure based on CD4 cell counts, clinical manifestations of disease progression, or both.¹³

Several studies from resource-limited settings have shown that lack of VL monitoring leads to frequent misclassification of failure and therefore, either premature switching to second-line regimen or a delay in change to second-line agents.^14-16

Current protocol

In India, as per the NACO guidelines, the patients stable on first-line regimen are monitored every six-months, and treatment monitoring includes weight, haemoglobin, alanine aminotransferase (ALT) and CD4 count. Routine pVL monitoring is not available. Patients suspected of having treatment failure for WHO-defined immunologic and clinical criteria are referred to select government HIV treatment centres designated as centre for excellence for viral load testing.¹⁷ If the patient is having virological failure (>10,000 copies/ml of HIV-RNA), he is switched to second-line regimen which is a combination of zidovudine or Tenofovir, lamivudine, and ritonavir-boosted atazanavir. The patients with low or undetectable viral load are continued with the same treatment.¹³

METHODS

A total of 50 patients, all above 18 years of age and receiving first line HAART for more than 1year and having WHO defined immunological failure i.e., their last reading of CD4 count falling down to pre-therapy baseline or if there was 50% fall from the on-treatment peak value or persistent CD4 levels below 100 cells/µl, were included in the current study after taking their informed written consent.Whole blood specimen of 50 patients was collected in ethylene diamine tetra acetic acid (EDTA) vacutainer by phlebotomy under aseptic conditions and plasma viral load was done using Roche Diagnostics’ RT-PCR Kit (COBAS® TaqMan® HIV-1 Test, version 2.0 (v2.0) with the high pure system as an in vitro nucleic acid amplification test).¹⁸

The patient was designated as virological failure depending upon the results of the plasma viral load. If the patient had high viral load (>10000 copies/ml), he was designated as having virological failure and if the viral load was low then he was designated as immunological failure. The prevalence of VF was calculated among WHO defined treatment failure cases.

RESULTS

Out of 50 cases, 30% were females and 70% were males; median age was 32.5 years; mean time on ART was 38.5months; mean baseline CD4 cell count was 139cells/mm³. The commonest first-line ART regimens were: zidovudine/lamivudine/nevirapine (AZT/ZDV+ 3TC+NVP) (40%) followed by zidovudine/Lamivudine/Efavirenz (ZDV+3TC+EFV) (18%) and Stavudine/Lamivudine/Nevirapine (d4T30+3TC+NVP) (16%). On the basis of plasma viral load testing, 8 (16%) of the total cases had treatment failure and these were designated as virological failures while the remaining 42 (84%) were classified as immunological failures only. Study subjects had a mean viral load of 0.62 X 10⁵ copies/ml at the time of study. The results of the study have been summarized in Table 2.

The Prevalence of virological failure among WHO defined immunological failure criteria was found to be 16%.

Some associated parameters in these 8 virological failure cases were analyzed. Out of the 8 cases, 6 belonged to age group 18-35 years and 2 belonged to 36-54 years’ age group. Even though, in our study, the cases of VF were more in the younger age group, this finding was not found to be statistically significant (p value>0.05)

It was observed in our study that number of cases of VF was more when the pre HAART CD4 count was <200 cells/mm³ (p value>0.05).

Among the patients with adherence more than 95%, only 4.9% cases had VF.

It was observed that poor adherence to treatment resulted in more cases of VF. This finding was found to be statistically significant (p value<0.05). The probability of developing virological failure was observed to be more, when the patient was co-infected with TB than when there was no HIV-TB co-infection. This observation was also found to be statistically significant (p value<0.05).

DISCUSSION

On the basis of plasma viral load testing, 8 (16%) of the total cases had treatment failure and these were designated as virological failures while the remaining 42(84%) were classified as immunological failures only. Study subjects had a mean viral load of 0.62X10⁵ copies /ml at the time of study.

A study conducted by Robbins et al showed that rate of VF was higher (42.5%) when the age of the patients was <40 years.¹⁹ In our study as well, the chances of VF dropped as the age of the patients progressed. The explanation behind the above findings may be that older patients might be more adherent to treatment.

The results of our study were in agrrement with Bello et al where the the percentage of developing virological failure was more when the pre treatmnet CD4 count was below 200cells/mm³.²⁰

Findings of our study were consistent with those of Paterson et al and Low Beer et al as the rate of VF decreased with increasing adherence (p value<0.001).²¹

The findings of Bello et al with regard to occurrence of increased chances of VF in patients who are co-infected with tuberculosis are in congruence with our findings and the same are also corroborated by the studies by Bekker et al, von Reyn et al and Ahoua et al which also showed that the mycobacterial disease was a major contributor to HIV mortality and VF is associated with occurrence of TB coinfection.^20,22-24

CONCLUSION

It could be seen that switch over to second line treatment would have been earlier, had there been early viral load testing, thus not wasting the precious time. It calls for the need to change the current treatment response monitoring protocol. It was also seen that factors like age, adherence, pre-HAART CD4 count and co infection with TB have greatly impacted the occurrence of virological failure and these can be used as predictors of virological failure in resource limited settings where routine plasma viral load monitoring is not possible.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethical Committee

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