To the Editors:
Antiretroviral therapy (ART) has demonstrated remarkable success in reducing morbidity and mortality associated with HIV infection.1,2 However, emergence of resistance to antiretroviral drugs (ARV) has tempered this success. The World Health Organization (WHO) recommends using a combination of 2 nucleoside/nucleotide reverse transcriptase inhibitors with ritonavir boosted protease inhibitors (PI/r) as second-line regimen.3 In randomized trials, the high efficacy of this regimen has been documented.4 However, data from low- and middle-income countries (LMIC) have demonstrated high rates of virological failure among patients on second-line regimens, predominantly driven by suboptimal adherence and prolonged exposure to previous regimens.5–8 For those failing with resistance, there is concern about accessing effective third-line regimens due to high levels of resistance to second-generation ARVs.5
According to the WHO, the demand for second- and third-line regimens will increase as access to viral load monitoring improves and early initiation of first-line ART continues to be scaled up. As the epidemic matures in LMIC, pilot studies are urgently needed on implementing third-line ART.
In India, second-line regimens were being used in private practice for many years, although the free program has scaled up use in the past 1 year. Significant failure rates to second-line regimens have been reported from Southern India.6 Newer ARVs, that is, darunavir (DRV) and raltegravir (RAL), have been available in India for the last few years making it possible to construct effective third-line regimens, although these are unavailable in the free program. Data about the effectiveness of third-line regimens in LMIC are limited. We report here the effectiveness of third-line regimens among patients in a LMIC setting of Western India.
This is a retrospective electronic chart review carried out at a tertiary-level private care center in Western India. The clinic provides comprehensive care to approximately 7000 HIV-infected patients. Patients pay out of pocket for accessing care including routine virological monitoring and genotypic resistance testing (GRT). ARVs and laboratory tests are provided at subsidized rates. All patients are offered an informed consent (approved by the Independent Ethics Committee) form mentioning that data collected during routine care may be used for research analysis.
To be eligible for analysis, patients had to be on third-line regimens for at least 6 months. Third-line regimens were constructed according to the principle of including at least 2 fully active ARVs, preferably from new classes. For all patients, third-line regimens consisted of RAL with a PI/r. Choice of PI/r was based on GRT results at second-line failure when available and/or pasttreatment history. Darunavir was used if there were <3 DRV-associated mutations. Before initiating a third-line regimen, patients readiness especially affordability was assessed. Adherence was assessed using self-report.
MEASUREMENTS AND DEFINITIONS
GRT was performed by in-house sequencing with external quality assurance program in place. After initiation of third-line regimens, CD4 count (determined by FACSCount; BD Bioscience) was performed every 6 months, whereas viral load (determined by Taqman) performed at 6 month and then annually. Virological success was defined as viral load <50 copies per milliliter, whereas failure was defined as reconfirmed viral load of more than 400 copies per milliliter. Loss to follow-up was defined as not seen in the clinic for more than a year. Primary outcome of the study was to determine the proportion of patients with virological success on third-line regimens. Secondary outcome included improvement in clinical status, CD4 counts, and safety.
Seventy-two patients were initiated on third-line regimens, 64 were expected to complete at least 6 months on treatment by March 31, 2013. Median [interquartile range (IQR)] age of patients was 40 years (36–49 years) and 80% were males. Median (IQR) duration since HIV diagnosis and on cumulative ART was 10.67 years (7.67–14.67 years) and 7.08 years (5.08–9.42 years), respectively. Median duration (IQR) on third-line regimen was 1.71 years (1.17–2.38 years). Pretherapy median (IQR) CD4 count was 88/mm3 (35–170) and median (IQR) log viral load was 4.59 (3.75–5.16).
GRT after second-line failure was available and used to design third-line regimens for 58 patients. Three patients had wild-type virus, whereas 21 patients did not have any PI resistance mutations documented. Frequency of major PI mutations included V32I-2, M46I/L-8, G48V-3, I50L-2, I54V-4, V82A-6, and N88S-1. Frequency of DRV-associated mutations included V11I-0, V32I-2, L33F-2, I47V-0, I50V-0, I54L-1, I54M-0, G73S-0, L76V-2, I84V-2, and L89V-0. No patients had more than 3 DRV-associated mutations.
Apart from RAL, the concomitant PI/r prescribed were Darunavir/ritonavir (DRV/r) (n = 30, 46.87%), ATV/r (n = 27, 42.1%), LPV/r (n = 7, 10.9%). All patients in the Atazanavir/ritonavir (ATV/r) group had received the same in second line and had no PI resistance documented on GRT.
Sixteen (25%) patients were lost to follow-up; majority did not visit the clinic after initiation of ART. Four patients died within 6 months of initiating ART (causes: intractable diarrhea, progressive multifocal leucoencephalopathy, tubercular meningitis, and interstitial lung disease with pulmonary hypertension and heart failure).
Proportion of patients with undetectable viral load at 6 and 18 months was 75.6% (95% CI 60.6%–86.1%) and 83% (95% CI 52%–98%) while median CD4 count gain at 6, 12 and 18 months were +211/mm3, +283/mm3, and +393/mm3, respectively (Fig. 1). One patient developed cyptococcal meningitis IRIS and another developed clinical hepatitis (on DRV/r), however, that was attributed to Acute HEV infection. Scleral icterus was documented in 48.1% patients with ATV/r. No patient discontinued the regimen due to toxicity.
Data on GRT were available for 3 patients failing the third-line regimen. All HIV-1 were subtype C. One patient had wild-type virus and 2 had major integrase inhibitor-associated mutations N155H and Q148H, respectively.
There is very limited data on the use of third-line regimens in LMICs.9 We have been able to demonstrate effectiveness of RAL + PI/r–based third-line regimens among patients failing PI/r-based second-line treatment. High rates of virological suppression were achieved with RAL-based regimens among treatment-experienced patients in the BENCHMRK studies.10 Pairing RAL with fully effective ARVs is crucial to achieve virological response.11 Other ARVs that could have contributed to potency of the third-line regimen like maraviroc and etravirine are unavailable in India. However, 2 fully active ARVs were adequate to ensure virological suppression.
The frequency of pretherapy PI mutations among patients failing second-line regimens was low in our study. For approximately 40% patients, we were able to achieve good results by combing RAL with the same PI/r (ATV/r) that was used in second line. Absence or limited PI resistance at second-line failure is due to virological monitoring in our clinic. In contrast, patients with significant baseline PI resistance were usually referred to us for the first time. However, other studies in India and LMICs have documented high levels of PI resistance among patients failing second-line regimens.5,6 This was mostly driven by limited virological monitoring of previous regimens.
We documented good effectiveness and safety of DRV/r in a subset of our patients. Frequency of DRV/r-associated mutations was low in our patients as has been reported in other Indian study.12 However, virological failure was more common with RAL + DRV/r–based regimen. This was due to suboptimal adherence, perhaps due to affordability issues and due to high pill burden compared with once daily ATV/r (available as a coformulation in India). The 400/800 mg formulation of DRV is unavailable in India; hence, once daily regimens could not be prescribed. Good clinical and virological outcomes with DRV/r-based regimens for third line has been documented in children and adults from Botswana and Brazil, respectively9,13
The predominant cause for loss to follow-up in our study was probably cost. The subsidized cost of RAL + ATV/r and RAL + DRV/r in or clinic is approximately 250 USD and 500 USD per month, respectively. In spite of adequate readiness assessment, patients may have found it difficult to afford. Early mortality after initiating ART may be another reason; however, we could not ascertain the same since we do not proactively trace patients lost to follow-up.
Our study has several limitations. Apart from the retrospective design and small sample size, patients who could afford third-line regimens may have different characteristics. It may not be possible to extrapolate these findings for other populations accessing ART through free programs.
In conclusion, we have demonstrated good short-term effectiveness and safety of third-line regimens in a small cohort of patients accessing care in Western India. However, this is in the context of availability of GRT and viral load to guide initiation and monitoring treatment success. After virological failure of the current WHO recommended second-line regimen, the combination of RAL and boosted PIs (esp DRV/r) would be effective third-line options. However, scaling up third-line regimens would need substantial cost reduction of ARVs and improving access to viral load and GRT testing in LMICs.
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