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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3181ba1b00
Letters to the Editor

Will Etravirine Work in Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor-Based Treatment in Southern Africa?

Stevens, Wendy S MD*; Wallis, Carole L MscMed*; Sanne, Ian MD†; Venter, Francois MD‡

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Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa, Clinical HIV Research Unit, University of the Witwatersrand Johannesburg, South Africa, Reproductive Health Research Unit University of the Witwatersrand Johannesburg, South Africa

To the Editor:

Little is known about the efficacy of second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) in sub-Saharan Africa, where antiretroviral resistance may be accentuated in the presence of limited viral load monitoring and delayed switching to second-line regimens. We evaluated the predicted efficacy of etravirine in a group of South African patients failing NNRTIs.

Countries in southern Africa rely on combinations of nucleoside and NNRTIs for first-line regimens with over half a million HIV-infected adults receiving NNRTI antiretroviral (ARV) treatment on the national program in South Africa by mid-2008 alone.1,2 In most of these countries, second-line is limited to boosted protease inhibitor-based regimens for patients failing first-line therapy. Many countries lack viral load monitoring or lack systems to quickly identify those failing therapy, leading to prolonged exposure to failing regimens and cumulative resistance. New compounds are required for all treatment programs as toxicity substitution, for those developing resistance, and to simplify regimens. Several novel compounds have recently been added to the ARV armamentarium in more resourced country treatment programs, including second-generation NNRTIs such as etravirine (TMC 125). Etravirine is a diarylypyrimidine compound with a high genetic barrier that has demonstrated efficacy in the face of resistance to first-generation NNRTIs.3,4

Recently, ARV resistance profiles have been described for 296 patients experiencing virologic failure in two clinics in Johannesburg accessing the South African national rollout program.5 Two hundred twenty-six patients in this group were accessing NNRTI-based regimens and were used for the analysis of predicted etravirine susceptibility. HIV drug resistance testing was performed using a population-based in-house sequencing assay.6

The following key etravirine mutations have been previously described: V179D/F, G190 A/S, Y181C/I/V, V106I, V179D/F, K101 E/P, A98G, V90I, E138A, M230L, and L100I.7-9 In these studies, virologic response decreased as the number of mutations increased with 77%, 61%, 56%, and 38% of patients achieving viral loads less than 50 HIV RNA copies/mL in the presence of zero, one, two, or three or more mutations, respectively. A new weighting score improves the correlation between genotype and phenotype and appears to correlate with virologic response with scores of 0 to 2, 2.5 to 3.5, and greater than 4 corresponding to virologic response rates of 74%, 52%, and 38%, respectively. Of the etravirine resistance-associated mutations described, Y181I and Y181V were given the highest weighting in this score followed by L100I, K101P, Y181C, and M230L. Both scoring algorithms were used in this analysis of the data in this population.

Within the group of 226 patients on failing NNRTI-based first-line regimens, the majority of the patients were accessing an efavirenz-based regimen (89% [n = 201]) and the remaining 25 patients were on a nevirapine-based regimen (11%). Of the 226 patients used in this analysis, 39% (n = 88) presented with mutations potentially altering susceptibility to etravirine. The overall prevalence of mutations were as follows: G190A: 29 (13%), K101E: 21(9%), V90I: 17 (8%), V179D: 17 (8%), Y181C: 12 (5%), A98G: eight (4%), L100I: six (3%), M230L: six (3%), G190S: six (3%), E138A: five (2%), 101H: four (2%), K101P: three (1%), V106I: three (1%), and Y181I: one (0.5%), with no patients harboring the Y181Vor V179F mutations. In summary, the most prevalent mutations were V90I, V179D, K101E, and G190A. Two mutations (V90I, 3.2% and G190A, 1.7%) are described at low levels in ARV drug-naïve subtype C patients (data not shown), whereas V179D and K101E have not and are therefore unlikely to be baseline polymorphisms.

Table 1 provides a summary of patients on each failing regimen with the number with etravirine mutations determined by the two different algorithms. When the weighting scoring system was used, 21 (9%) patients would present with reduced susceptibility to etravirine, whereas using the other algorithm, 5% of patients (n = 11) would have had reduced susceptibility to etravirine.

Table 1
Table 1
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In conclusion, these data suggest (irrespective of which algorithm used) that over 90% of patients previously exposed to efavirenz or nevirapine in the southern African treatment programs would remain susceptible to etravirine despite prolonged exposure to first-line NNRTI-based regimens. However, future use of this drug in this region is likely to depend on cost and availability.

Wendy S. Stevens, MD*

Carole L. Wallis, MScMed*

Ian Sanne, MD†

Francois Venter, MD‡

*Department of Molecular Medicine and Haematology

University of the Witwatersrand

Johannesburg, South Africa

†Clinical HIV Research Unit

University of the Witwatersrand

Johannesburg, South Africa

‡Reproductive Health Research Unit

University of the Witwatersrand

Johannesburg, South Africa

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REFERENCES

1. National Comprehensive HIV and AIDS Treatment Plan Statistics: August 2008 Report. Health Information, Evaluation and Research Division, Department of Health. Available at: http://www.doh.gov.za/docs/statistics.pdf. Accessed January 12, 2009.

2. National Department of Health. National Antiretroviral Treatment Guidelines, 1st ed; 2004. Available at: http://www.doh.gov.za/aids/index.html. Accessed January 12, 2009.

3. Seminari E, Castagna A, Lazzarin A. Etravirine for the treatment of HIV infection. Expert Rev Anti Infect Ther. 2008;6:427-433.

4. Jayaweera DT, Espinoza L, Castro J. Etravirine: the renaissance of non-nucleoside reverse transcriptase inhibitors. Expert Opin Pharmacother. 2008;9:3083-3094.

5. Wallis CL, Mellors JW, Venter WDF, et al. Varied patterns of HIV-1 drug resistance among patients on failing first-line antiretroviral therapy in the South African national roll-out programme. Antiviral Therapy. 2009;14(Suppl 1):A181.

6. Wallis C, Papathanasopoulos M, Rinke de Wit T, et al. Subtype C specific In-house HIV-1 Drug Resistance Assay. 5th European HIV Drug Resistance Workshop; March 28-30, 2007, Cascais, Portugal.

7. Lapadula G, Calabresi A, Castelnuovo F, et al. Prevalence and risk factors for etravirine resistance among patients failing on non-nucleoside reverse transcriptase inhibitors. Antivir Ther. 2008;13:601-605.

8. Llibre JM, Santos JR, Puig T, et al. Prevalence of etravirine-associated mutations in clinical samples with resistance to nevirapine and efavirenz. J Antimicrob Chemother. 2008;62:909-913.

9. Vingerhoets J, Peeters P, Azijn H, et al. An update of the list of NNRTI mutations associated with decreased virologic response to etravirine (ETR): multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data. Antiviral Therapy. 2008;13(Suppl 3):A25.

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© 2009 Lippincott Williams & Wilkins, Inc.

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