Chronic hepatitis C treatment outcomes in low- and middle-income countries: a systematic review and meta-analysis

Résultats du traitement de l'hépatite C chronique dans les pays à revenu faible et moyen: évaluation systématique et méta-analyse

Resultados del tratamiento de la hepatitis C crónica en países de ingresos medios y bajos: examen sistemático y meta-análisis

Nathan Ford^I*; Catherine Kirby^I; Kasha Singh^II; Edward J Mills^III; Graham Cooke^IV; Adeeba Kamarulzaman^V; Philipp duCros^VI

ABSTRACT

OBJECTIVE: To assess the effectiveness of treatment for hepatitis C virus (HCV) infection in low- and middle-income countries and identify factors associated with successful outcomes. ]]> METHODS: We performed a systematic review and meta-analysis of studies of HCV treatment programmes in low- and middle-income countries. The primary outcome was a sustained virological response (SVR). Factors associated with treatment outcomes were identified by random-effects meta-regression analysis.
FINDINGS: The analysis involved data on 12 213 patients included in 93 studies from 17 countries. The overall SVR rate was 52% (95% confidence interval, CI: 48-56). For studies in which patients were predominantly infected with genotype 1 or 4 HCV, the pooled SVR rate was 49% (95% CI: 43-55). This was significantly lower than the rate of 59% (95% CI: 54-64) found in studies in which patients were predominantly infected with other genotypes (P = 0.012). Factors associated with successful outcomes included treatment with pegylated interferon and ribavirin, infection with an HCV genotype other than genotype 1 or 4 and the absence of liver damage or human immunodeficiency virus infection at baseline. No significant difference in the SVR rate was observed between weight-adjusted and fixed-dose ribavirin treatment. Overall, 17% (95% CI: 13-23) of adverse events resulted in treatment interruption or dose modification, but only 4% (95% CI: 3-5) resulted in treatment discontinuation.
CONCLUSION: The outcomes of treatment for HCV infection in low- and middle-income countries were similar to those reported in high-income countries.

RÉSUMÉ

OBJECTIF: Évaluer l'efficacité du traitement de l'infection par le virus de l'hépatite C (VHC) dans les pays à revenu faible et moyen et identifier les facteurs associés aux résultats positifs.
MÉTHODES: Nous avons effectué une évaluation systématique et une méta-analyse des études sur les programmes de traitement du VHC dans les pays à revenu faible et moyen. Le résultat principal consistait en une réponse virologique soutenue (RVS). Les facteurs liés aux résultats du traitement ont été identifiés à l'aide d'une analyse de méta-régression des effets aléatoires.
RÉSULTATS: L'analyse portait sur les données de 12 213 patients inclus dans 93 études provenant de 17 pays différents. Le taux de RVS général était de 52% (intervalle de confiance de 95%, IC: 48-56). Pour les études dans lesquelles les patients étaient principalement atteints par le VHC de génotype 1 ou 4, le taux de RVS groupé était de 49% (IC de 95%: 43-55). Ce taux était largement inférieur à celui de 59% (IC de 95%: 54-64) présenté dans les études dans lesquelles les patients étaient principalement atteints par d'autres génotypes (P = 0,012). Les facteurs liés aux résultats positifs incluaient le traitement à l'interféron pégylé et à la ribavirine, l'infection à un VHC de génotype autre que 1 ou 4 et l'absence de lésions au foie ou d'infection par le virus de l'immunodéficience humaine initialement. Aucune différence significative dans le taux de RVS n'a été observée entre les traitements de ribavirine adaptés au poids et ceux à dose fixe. Dans l'ensemble, 17% (IC de 95%: 13-23) des effets indésirables ont entraîné une interruption du traitement ou une modification des doses, tandis que 4% (IC de 95%: 3-5) d'entre eux ont entraîné un abandon du traitement.
CONCLUSION: Les résultats du traitement de l'infection du VHC dans les pays à revenu faible et moyen étaient similaires à ceux qui étaient indiqués dans les pays à revenu élevé.

RESUMEN

OBJETIVO: Determinar la efectividad del tratamiento para la infección por el virus de la hepatitis C (VHC) en países de ingresos medios y bajos e identificar los factores asociados con unos resultados satisfactorios. ]]> MÉTODOS: Realizamos un examen sistemático y un meta-análisis de estudios de programas de tratamiento del VHC en países de ingresos medios y bajos. El resultado fundamental fue una respuesta viral sostenida (RVS). Los factores asociados con los resultados del tratamiento se identificaron mediante un análisis de metarregresión de efectos aleatorios.
RESULTADOS: El análisis incluyó datos sobre 12 213 pacientes en 93 estudios de 17 países. La tasa global de RVS fue del 52% (intervalo de confianza, IC del 95%: 48-56). Para estudios en los que los pacientes estaban predominantemente infectados con VHC del genotipo 1 o 4, la tasa de RVS combinada fue del 49% (IC del 95%: 43-55). Esta fue significativamente menor que la tasa del 59% (IC del 95%: 54-64) encontrada en estudios en los que los pacientes estaban predominantemente infectados con otros genotipos (P = 0,012). Los factores asociados con los resultados satisfactorios incluyeron el tratamiento con interferón pegilado y ribavirina, la infección del VHC de un genotipo distinto al 1 o al 4 y la ausencia de lesión hepática o de infección por el virus de la inmunodeficiencia humana en el inicio. No se observaron diferencias significativas en la tasa de RVS entre el tratamiento de ribavirina adaptado al peso del paciente y el de dosis fijas. En conjunto, el 17% (IC del 95%: 13-23) de los eventos adversos provocó la interrupción del tratamiento o la modificación de la dosis, mientras que el 4% (IC del 95%: 3-5) causó el abandono del tratamiento.
CONCLUSIÓN: Los resultados del tratamiento de la infección del VHC en países de ingresos bajos y medios fueron similares a los de países de ingresos elevados.

Introduction

Hepatitis C virus (HCV) infection is a growing public health concern. Globally an estimated 180 million people, or roughly 3% of the world's population, are currently infected.¹ The burden of disease is greatest in developing countries: the highest reported prevalences are in China (3.2%), Egypt (22%) and Pakistan (4.8%).²

Most of the disease burden associated with HCV infection results from the development of chronic liver disease, sometimes leading to end-stage liver disease (cirrhosis), and standardized mortality ratios for liver-related death are 16- to 46-fold higher in infected individuals than in the general population.^5-7 The complications of cirrhosis include liver failure, hepatocellular carcinoma and death.^8,9 Approximately 20% of HCV-infected patients will experience complications.^10-12Successful treatment can improve liver fibrosis and cirrhosis, help prevent hepatocellular carcinoma and even clear the virus.¹³ Treatment can also contribute to disease prevention by reducing the reservoir of infected individuals who can transmit the virus.

Despite the benefits of treatment, there is reluctance to making it more widely available in resource-limited settings because of fears that treatment success rates will be low and because treatment is complex, costly and produces side-effects.¹⁴ In addition, outcomes are often poor in patients coinfected with the human immunodeficiency virus (HIV).¹⁵

We performed a systematic review and meta-analysis of reported treatment outcomes in HCV-infected patients in low- and middle-income countries. The aims were to assess the feasibility of providing treatment for HCV infection in less well-resourced settings and to identify factors associated with successful treatment outcomes.

Methods

The PubMed and Embase databases were searched for articles on observational studies that reported sustained virological response (SVR) rates in adult patients with chronic HCV infection and that were performed in a low- or middle-income country, as defined by The World Bank classification.¹⁶ Both cohort studies and case series including 10 or more patients were considered for inclusion. An SVR was defined as the absence of detectable HCV in blood 24 weeks after the completion of antiviral therapy.

The databases were searched using a predefined protocol (Appendix A, available at: http://www.msfaccess.org/sites/default/files/MSF_assets/HIV_AIDS/Docs/AIDS_MedJourn_HCVtreatmentReview_ENG_2011.pdf ) using the terms hepatitis C, HCV, treatment, therapy, interferon, sustained virological response and SVR. In addition, the bibliographies of relevant articles were reviewed. Preliminary searches were carried out independently by two of the study authors, who decided whether a publication was eligible for inclusion in the systematic review by evaluating its title using predefined criteria. If there was any uncertainty, all the study authors were consulted to reach a consensus on eligibility.

Because the aim of the systematic review was to describe the outcomes of HCV treatment administered within a clinical programme, we included observational cohort studies that reported treatment outcomes and excluded studies with an experimental design. We also excluded studies that reported outcomes in specific patient groups, such as patients with comorbid conditions, with prior treatment, or with known treatment resistance. However, because of concerns about HCV infection in HIV-infected individuals, studies on patients coinfected with HIV were included in the review.

Data extraction

Each cohort was divided into categories in accordance with the following discrete clinical variables: (i) whether standard or pegylated interferon was administered, irrespective of the type of interferon; (ii) whether fixed-dose or weight-adjusted ribavirin was administered; (iii) whether treatment lasted less than 24 weeks or longer; (iv) whether fewer than or more than 50% of patients in the study cohort were HIV-positive (HIV+); (v) whether fewer than or more than 50% of patients in the study cohort were infected with genotype 1 or 4 (these genotypes are associated with a poor response to treatment); and (vi) whether fewer than or more than 50% of patients in the study cohort had bridging fibrosis, an indicator of the extent of liver damage, at baseline. In addition, information was also sought on the presence of the interleukin-28B gene polymorphism, which is as an important determinant of treatment success.

The methodological quality of the studies included in the systematic review was assessed on the basis of the study design (i.e. retrospective or prospective), the reporting of disease status at baseline, the proportion of patients who completed treatment, and consideration of potential confounding. Finally, information on sources of funding were extracted to give an indication of the potential replicability and sustainability of the treatment programme. Any uncertainty surrounding the data was resolved by contacting the study authors.

Statistical analysis

Point estimates and 95% confidence intervals (CIs) were derived for all outcomes. The SVR rates were calculated on an intention-to-treat basis, with all patients who initiated therapy being included in the denominator of the calculation. The variance in the raw proportion was stabilized using a Freeman-Tukey-type arcsine square-root transformation¹⁷ and these proportions were pooled using a DerSimonian-Laird random-effects model.¹⁸ The τ² statistic was calculated to assess the proportion of the overall variation that was attributable to between-study heterogeneity.^19,20 Since pooling proportions can yield high rates of heterogeneity, we explored the potential influence of clinical and programmatic covariates that had been identified a priori through random-effects method-of-moments meta-regression²¹ and univariate subgroup analyses. Subgroup analyses were used to assess the potential influence of the following covariates: treatment regimen, HIV status, HCV genotype, liver damage at baseline, level of economic development of the study region, geographical location of the study region and study design (i.e. prospective or retrospective). All reported P-values are two-sided and significance was set at P < 0.05. All analyses were performed using Stata version 11 (StataCorp. LP, College Station, United States of America).

Results

Study characteristics

Our search found 1216 articles. After evaluation, 93 studies, which involved a total of 12 213 patients, met our inclusion criteria and were carried through to the meta-analysis (Fig. 1). Although the studies covered 17 countries, some were more frequently represented: there were 19 studies from Brazil, 17 from Pakistan, 13 from Egypt, 12 from China and 10 from India.

Around half of the studies (i.e. 46 studies involving 5995 patients) included patients who were predominantly infected with HCV genotype 1 or 4. Ten studies failed to adequately report on viral genotype. Patients were treated with ribavirin and interferon in 86 studies, while interferon alone was given in 7 studies: pegylated interferon was administered in 52 and standard interferon was used in 44. The extent of liver damage at baseline was reported in 33 studies, together comprising 2407 patients. In addition, although 54 studies gave details of patients' HIV status, only 3, which included 105 patients in total, reported outcomes among HIV-infected individuals. Two studies included data on outcomes in patients with and without the interleukin-28B gene polymorphism.

We judged the quality of the studies included in the meta-analysis to be moderate. The majority (i.e. 65 studies) reported prospectively collected data, 72 detailed disease progression at baseline, 77 considered potential confounding factors and 89 stated that > 80% of patients completed treatment.

Of the 29 studies that reported sources of funding, 18 were supported by national government funds, 4 received pharmaceutical industry funding, 1 was supported by an international research grant, 1 by a charitable grant and 5 stated that the study received no specific funding. A table summarizing each study's characteristics is available in Appendix B, at: http://www.msfaccess.org/sites/default/files/MSF_assets/CAME/Access_Data_StudyCharacteristics_ENG_2012.pdf.

Study outcomes

Overall, 52% (95% CI: 48-56) of patients achieved an SVR. However, the between-study heterogeneity in the SVR rate was high (τ²: 410), as expected for observational data. For studies in which patients were predominantly infected with HCV genotype 1 or 4, the proportion of patients who achieved an SVR ranged from 4% (95% CI: 1-9)²² to 79% (95% CI: 66-89)²³ and the pooled proportion was 49% (95% CI: 43-55). For studies in which patients were predominantly infected with HCV genotypes other than 1 or 4, the SVR rate ranged from 16% (95% CI: 10-24)²⁴ to 86% (95% CI: 77-93)²⁵ and the pooled proportion of these patients who achieved an SVR was 59% (95% CI: 54-64), which was significantly higher than among patients infected with HCV genotype 1 or 4 (P = 0.012). Since the treatment duration was found to be collinear with viral genotype, it was not considered in the analysis.

Fig. 2 summarizes how the SVR rate was influenced by HCV treatment, viral genotype, liver damage at baseline, HIV status, the level of economic development and the geographical location of the study region. Univariate meta-regression analysis showed that the proportion of patients who achieved an SVR varied significantly with the formulation of the interferon administered (i.e. standard or pegylated), ribavirin use, viral genotype, the severity of liver damage at baseline, HIV status and the level of economic development of the study region (Table 1). Viral genotype and HIV status were still found to be significantly associated with the SVR rate on multivariate analysis, but other factors were not. Further, subgroup analyses showed that the best outcomes were achieved in studies in which patients were either predominantly HIV-negative (HIV-), predominantly infected with an HCV genotype other than 1 or 4, or treated with ribavirin. The proportion of patients who achieved an SVR in the 20 studies that included patients with all three of these characteristics ranged from 45% (95% CI: 34-55)⁷⁰ to 78% (95% CI: 61-91)⁷¹ and the pooled proportion was 65% (95% CI: 61-68). The presence of the interleukin-28B polymorphism was associated with a high SVR rate in the two studies which reported relevant data.^26,72

End-of-treatment responses were recorded in 49 studies. The pooled estimate of the proportion of patients who achieved an end-of-treatment response was higher: (i) for those who were HIV- than for those who were HIV+, at 74% versus 52%, respectively; (ii) for those who received ribavirin than for those who did not, at 69% versus 51%, respectively; and (iii) for those who received pegylated rather than standard interferon, at 73% versus 62%, respectively. Overall, 53% (95% CI: 47-58) of patients who achieved an end-of-treatment response went on to achieve an SVR. This rate was significantly greater in patients who were treated with pegylated interferon (i.e. 57%; 95% CI: 52-63) than in those who received standard interferon (i.e. 47%; 95% CI: 38-56) and in those who were HIV- (i.e. 59%; 95% CI: 53-64) than in those who were HIV+ (i.e. 35%; 95% CI: 30-40). However, neither viral genotype (P = 0.2), ribavirin treatment (P = 0.6) nor liver damage at baseline (P = 0.4) influenced the proportion that went on to achieve an SVR.

Adverse events that resulted in treatment interruption or dose modification were reported in 16 studies and were experienced by 17% (95%CI: 13-23) of patients in these studies. The drug regimen had no significant effect on the proportion of these adverse events. Adverse events that resulted in treatment termination were reported in 39 studies and were experienced by 4% of patients (95% CI: 3-5). These adverse events were significantly more common in patients who were taking weight-adjusted ribavirin than in those taking fixed-dose ribavirin (4% versus 2%, respectively; P < 0.0001). Table 2 lists the most serious adverse events that led to treatment discontinuation in individual studies.

Overall, 39 studies reported losses to follow-up. The rate was generally low and the pooled proportion of patients reported as lost to follow-up was 4% (95% CI: 3-4). In addition, mortality was also low: less than 1% (95% CI: 0.1-1) of patients were reported to have died during the observation period.

Discussion

Our systematic review found many reports of HCV treatment programmes in low- and middle-income countries involving substantial numbers of patients. They indicated that the programmes had been successful. Notably, most of the studies that gave information on funding sources reported funding from domestic public sources. This observation is consistent with recent survey data indicating that partial or total government funding is available for hepatitis treatment in 69% of countries worldwide and in more than 50% of countries in all WHO regions except the WHO African Region.³ We found that overall 52% of patients treated in low- and middle-income countries achieved an SVR, which is similar to the rate reported in high-income countries. For example, in developed countries, the average SVR rate observed in clinical trials of patients with HCV genotype 1 infections after 48 weeks of treatment with pegylated interferon and weight-adjusted ribavirin ranged from 45% to 48%, while it ranged from 22% to 31% after 24 weeks of treatment.¹¹⁶

As found in other studies, the most important determinants of treatment success were infection with an HCV genotype other than 1 or 4, the absence of liver damage at baseline, an HIV- status and treatment with pegylated interferon and ribavirin.¹¹⁶ The geographical variations in outcomes we observed were probably due to a combination of these factors. Although, as expected, treatment with pegylated interferon and ribavirin was associated with better outcomes than treatment with other regimens, the use of weight-adjusted rather than fixed-dose ribavirin offered no observable advantage. Moreover, despite reports that HCV treatment is associated with significant side-effects, only 4% of patients included in our meta-analysis discontinued treatment because of adverse events. The observation that clinical rather than geographical factors were the most important determinants of treatment success suggests that good outcomes can be achieved with current regimens in resource-limited settings and offers support to calls for better access to diagnosis and treatment in these settings.¹¹⁷

Furthermore, the substantial heterogeneity in results we observed between studies limited the validity of this analysis, as it made it more difficult to determine the magnitude of the relative influence of individual factors on treatment success. In addition, we may have missed some studies because we searched a limited number of databases and our review excluded studies that reported outcomes in patients who were coinfected with a non-HIV agent that may have influenced treatment outcomes, such as the hepatitis B virus. Finally, our analysis was also limited by inconsistent reporting of secondary outcomes. Future studies should report rapid virological responses, end-of-treatment responses, adverse events and losses to follow-up. Data on rapid virological responses would help inform decisions on whether to shorten treatment.¹¹⁴

Given these limitations, our review should not be taken as representative of all low- and middle-income countries. It does, however, illustrate the range of treatment outcomes that can be achieved in settings with limited resources.

With currently available regimens, the treatment success rate achievable in patients infected with an HCV genotype other than 1 and 4 is in line with or better than the success rate achieved with other chronic infections that cause substantial morbidity in resource-limited settings, such as multidrug-resistant tuberculosis.¹¹⁸ However, currently the cost of treatment is a major barrier: a 48-week course of pegylated interferon and ribavirin costs as much in Thailand as in the United Kingdom of Great Britain and Northern Ireland (i.e. around 17 000 United States dollars). Treatment with recently approved protease inhibitors substantially improves success rates and these drugs are now the standard of care for patients with HCV genotype 1 infections in resource-rich settings, but they are even more expensive.¹¹⁹ In a recent survey in low-income countries, four out of five ministries of health identified the need for financial assistance to increase access to treatment for viral hepatitis as a priority.³ Future research on barriers to obtaining medicines for the treatment of HCV infection in resource-limited settings should be encouraged.

New protease and polymerase inhibitors currently under investigation offer the potential for oral therapy that will further improve the SVR rate in patients with HCV infection and may also reduce both treatment complexity and adverse events.¹²⁰ These drugs will be particularly useful in resource-limited settings where the disease burden is greatest. Given that HCV treatment can be successful in these settings, the early introduction of new therapies in countries with limited resources should be an important consideration during drug development. In the past, mechanisms for decreasing the cost of and improving access to medicines for chronic infections such as multidrug-resistant tuberculosis and HIV/AIDS have been established; similar mechanisms should be considered for HCV infection.

In summary, our review found that patients with an HCV infection in resource-limited settings have treatment success rates similar to those in developed countries. This observation provides further justification for increasing efforts to improve access to HCV treatment in low- and middle-income countries.

References

1. Hadigan C, Kottilil S. Hepatitis C virus infection and coinfection with human immunodeficiency virus: challenges and advancements in management. JAMA 2011;306:294-301. doi:10.1001/jama.2011.975 PMID:21771990        [ Links ]

2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5:558-67. doi:10.1016/S1473-3099(05)70216-4 PMID:16122679        [ Links ]

3. Viral hepatitis: global policy. London: World Hepatitis Alliance; 2011. Available from: http://www.worldhepatitisalliance.org/Policy/2010PolicyReport.aspx[accessed 12 January 2012]         [ Links ].

4. Viral hepatitis. WHA63.18. Sixty-third World Health Assembly. Agenda item 11.12. Geneva: World Health Organization; 2010. Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R18-en.pdf[accessed 12 January 2012]         [ Links ].

5. Amin J, Law MG, Bartlett M, Kaldor JM, Dore GJ. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006;368:938-45. doi:10.1016/S0140-6736(06)69374-4 PMID:16962883        [ Links ]

6. Duberg AS, Torner A, Davidsdottir L, Aleman S, Blaxhult A, Svensson A et al. Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study. J Viral Hepat 2008;15:538-50. doi:10.1111/j.1365-2893.2008.00982.x PMID:18397223        [ Links ]

7. McDonald SA, Hutchinson SJ, Bird SM, Mills PR, Dillon J, Bloor M et al. A population-based record linkage study of mortality in hepatitis C-diagnosed persons with or without HIV coinfection in Scotland. Stat Methods Med Res 2009;18:271-83. doi:10.1177/0962280208094690 PMID:19036907        [ Links ]

8. John-Baptiste A, Krahn M, Heathcote J, Laporte A, Tomlinson G. The natural history of hepatitis C infection acquired through injection drug use: meta-analysis and meta-regression. J Hepatol 2010;53:245-51. doi:10.1016/j.jhep.2010.03.015 PMID:20537752        [ Links ]

9. Massard J, Ratziu V, Thabut D, Moussalli J, Lebray P, Benhamou Y et al. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol 2006;44(Suppl):S19-24. doi:10.1016/j.jhep.2005.11.009 PMID:16356583        [ Links ]

10. Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci 2006;3:47-52. doi:10.7150/ijms.3.47 PMID:16614742        [ Links ]

11. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-74. doi:10.1002/hep.22759 PMID:19330875        [ Links ]

12. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008;48:418-31. doi:10.1002/hep.22375 PMID:18563841        [ Links ]

13. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011;52:889-900. doi:10.1093/cid/cir076 PMID:21427396        [ Links ]

14. Cooper CL, Mills E, Wabwire BO, Ford N, Olupot-Olupot P. Chronic viral hepatitis may diminish the gains of HIV antiretroviral therapy in sub-Saharan Africa. Int J Infect Dis 2009;13:302-6. doi:10.1016/j.ijid.2008.06.042 PMID:19004656        [ Links ]

15. Operskalski EA, Kovacs A. HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies. Curr HIV/AIDS Rep 2011;8:12-22. doi:10.1007/s11904-010-0071-3 PMID:21221855        [ Links ]

16. Country and lending groups [Internet]. Washington: World Bank; 2011. Available from: http://data.worldbank.org/about/country-classifications/country-and-lending-groups[accessed 12 January 2012]         [ Links ].

17. Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Inst Stat Math 1950;21:607-11.         [ Links ]

18. Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res 1993;2:121-45. doi:10.1177/096228029300200202 PMID:8261254        [ Links ]

19. Walters DE. The need for statistical rigour when pooling data from a variety of sources. Hum Reprod 2000;15:1205-6. doi:10.1093/humrep/15.5.1205 PMID:10783380        [ Links ]

20. Rücker G, Schwarzer G, Carpenter JR, Schumacher M. Undue reliance on I(2) in assessing heterogeneity may mislead. BMC Med Res Methodol 2008;8:79. doi:10.1186/1471-2288-8-79 PMID:19036172        [ Links ]

21. Borenstein M, Hedges L, Higgins J, Rothstein H. Meta-regression. In: Borenstein M, Hedges LV, Higgins JPT, Rothstein HR, editors. Introduction to meta-analysis. Chichester: Wiley; 2009. pp.190-202.         [ Links ]

22. El-Zayadi A, Simmonds P, Dabbous H, Prescott L, Selim O, Ahdy A. Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4. J Viral Hepat 1996;3:261-4. doi:10.1111/j.1365-2893.1996.tb00052.x PMID:8914006        [ Links ]

23. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009;136:856-62. doi:10.1053/j.gastro.2008.11.037 PMID:19135998        [ Links ]

24. Jiao J, Wang JB. Hepatitis C virus genotypes, HLA-DRB alleles and their response to interferon-alpha and ribavirin in patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2005;4:80-3. PMID:15730926        [ Links ]

25. Mishra PK, Bhargava A, Khan S, Pathak N, Punde RP, Varshney S. Prevalence of hepatitis C virus genotypes and impact of T helper cytokines in achieving sustained virological response during combination therapy: a study from central India. Indian J Med Microbiol 2010;28:358-62. doi:10.4103/0255-0857.71813 PMID:20966569        [ Links ]

26. Chen JY, Lin CY, Wang CM, Lin YT, Kuo SN, Shiu CF et al. IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-alpha plus ribavirin therapy in Taiwanese chronic HCV infection. Genes Immun 2011;12:300-9. doi:10.1038/gene.2011.1 PMID:21346780        [ Links ]

27. Ahmed WU, Arif A, Qureshi H, Alam SE, Ather R, Fariha S et al. Factors influencing the response of interferon therapy in chronic hepatitis C patients. J Coll Physicians Surg Pak 2011;21:69-73. PMID:21333235        [ Links ]

28. Akbar H, Idrees M, Butt S, Awan Z, Sabar MF, Rehaman IU et al. High baseline interleukine-8 level is an independent risk factor for the achievement of sustained virological response in chronic HCV patients. Infect Genet Evol 2011;11:1301-5. doi:10.1016/j.meegid.2011.04.021 PMID:21554996        [ Links ]

29. Akram M, Idrees M, Zafar S, Hussain A, Butt S, Afzal S et al. Effects of host and virus related factors on interferon-alpha+ribavirin and pegylated-interferon+ribavirin treatment outcomes in chronic hepatitis C patients. Virol J 2011;8:234. doi:10.1186/1743-422X-8-234 PMID:21575275        [ Links ]

30. Ali I, Khan S, Attaullah S, Khan SN, Khan J, Siraj S et al. Response to combination therapy of HCV 3a infected Pakistani patients and the role of NS5A protein. Virol J 2011;8:258. doi:10.1186/1743-422X-8-258 PMID:21609495        [ Links ]

31. Ali L, Mansoor A, Ahmad N, Siddiqi S, Mazhar K, Muazzam AG et al. Patient HLA-DRB1* and -DQB1* allele and haplotype association with hepatitis C virus persistence and clearance. J Gen Virol 2010;91:1931-8. doi:10.1099/vir.0.018119-0 PMID:20392899        [ Links ]

32. Amarapurkar D, Dhorda M, Kirpalani A, Amarapurkar A, Kankonkar S. Prevalence of hepatitis C genotypes in Indian patients and their clinical significance. J Assoc Physicians India 2001;49:983-5. PMID:11848330        [ Links ]

33. Antaki N, Hermes A, Hadad M, Ftayeh M, Antaki F, Abdo N et al. Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5. J Viral Hepat 2008;15:383-6. doi:10.1111/j.1365-2893.2007.00946.x PMID:18086180        [ Links ]

34. Bouzgarrou N, Hassen E, Mahfoudh W, Gabbouj S, Schvoerer E, Ben Yahia A et al. NS5A(ISDR-V3) region genetic variability of Tunisian HCV-1b strains: correlation with the response to the combined interferon/ribavirin therapy. J Med Virol 2009;81:2021-8. doi:10.1002/jmv.21641 PMID:19856481        [ Links ]

35. Dai CY, Chuang WL, Chang WY, Chen SC, Lee LP, Hsieh MY et al. Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin. World J Gastroenterol 2005;11:4241-5. PMID:16015698        [ Links ]

36. David J, Rajasekar A, Daniel HD, Ngui SL, Ramakrishna B, Zachariah UG et al. Infection with hepatitis C virus genotype 3 - experience of a tertiary health care centre in south India. Indian J Med Microbiol 2010;28:155-7. doi:10.4103/0255-0857.62495 PMID:20404464        [ Links ]

37. El-Zayadi A, Selim O, Hamdy H, El-Tawil A, Badran HM, Attia M et al. Impact of cigarette smoking on response to interferon therapy in chronic hepatitis C Egyptian patients. World J Gastroenterol 2004;10:2963-6. PMID:15378774        [ Links ]

38. El-Zayadi AR, Attia M, Barakat EM, Badran HM, Hamdy H, El-Tawil A et al. Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005;100:2447-52. doi:10.1111/j.1572-0241.2005.00253.x PMID:16279899        [ Links ]

39. Gallegos-Orozco JF, Loaeza-del Castillo A, Fuentes AP, Garcia-Sandoval M, Soto L, Rodriguez R et al. Early hepatitis C virus changes and sustained response in patients with chronic hepatitis C treated with peginterferon alpha-2b and ribavirin. Liver Int 2005;25:91-5. doi:10.1111/j.1478-3231.2005.1040.x PMID:15698404        [ Links ]

40. Gong GZ, Lai LY, Jiang YF, He Y, Su XS. HCV replication in PBMC and its influence on interferon therapy. World J Gastroenterol 2003;9:291-4. PMID:12532451        [ Links ]

41. Hazari S, Panda SK, Gupta SD, Batra Y, Singh R, Acharya SK. Treatment of hepatitis C virus infection in patients of northe\rn India. J Gastroenterol Hepatol 2004;19:1058-65. doi:10.1111/j.1440-1746.2004.03405.x PMID:15304125        [ Links ]

42. Idrees M, Riazuddin S. A study of best positive predictors for sustained virologic response to interferon alpha plus ribavirin therapy in naive chronic hepatitis C patients. BMC Gastroenterol 2009;9:5. doi:10.1186/1471-230X-9-5 PMID:19152711        [ Links ]

43. Iqbal SKU-R, Dogar MZ, Bashir S, Akhtar M. Sustained biochemical and virological response of different HCV genotypes to Interferon-alpha plus ribavirin combination therapy Pharmacologyonline 2010;2:161-9.         [ Links ]

44. Kalantari H, Kazemi F, Minakari M. Efficacy of triple therapy with interferon alpha-2b, ribavirin and amantadine in the treatment of naïve patients with chronic hepatitis C. J Res Med Sci 2007;12:178-85.         [ Links ]

45. Khalid SR, Khan AA, Alam A, Lak NH, Butt AK, Shafqat F et al. Interferon-ribavirin treatment in chronic hepatitis C - the less talked about aspects. J Ayub Med Coll Abbottabad 2009;21:99-102. PMID:20524481        [ Links ]

46. Khan AA, Sarwar S. Response to combination therapy in hepatitis virus C genotype 2 and 3. J Coll Physicians Surg Pak 2009;19:473-7. PMID:19651007        [ Links ]

47. Khokhar N. Effectiveness of 48 weeks interferon alfa-2b in combination with ribavirin as initial treatment of chronic hepatitis. J Ayub Med Coll Abbottabad 2002;14:5-8. PMID:12476854        [ Links ]

48. Muhammad N, Jan MA, Rahman N. Outcome of combined interferon-ribavirin in the treatment of chronic hepatitis C. J Coll Physicians Surg Pak 2004;14:651-3. PMID:15530272        [ Links ]

49. Petrenkiene V, Gudinaviciene I, Jonaitis L, Kupcinskas L. Interferon alpha-2b in combination with ribavirin for the treatment of chronic hepatitis C: assessment of virological, biochemical and histological treatment response. Medicina (Kaunas) 2004;40:538-46. PMID:15208476        [ Links ]

50. Pramoolsinsap C, Poovorawan Y, Sura T, Theamboonlers A, Busagorn N, Kurathong S. Hepatitis G infection and therapeutic response to interferon in HCV-related chronic liver disease. Southeast Asian J Trop Med Public Health 1998;29:480-90. PMID:10437943        [ Links ]

51. Qureshi S, Batool U, Iqbal M, Qureshi O, Kaleem R, Aziz H et al. Response rates to standard interferon treatment in HCV genotype 3a. J Ayub Med Coll Abbottabad 2009;21:10-4. PMID:21067014        [ Links ]

52. Sarwar S, Butt AK, Khan AA, Alam A, Ahmad I, Dilshad A. Serum alanine aminotransferase level and response to interferon-ribavirin combination therapy in patients with chronic hepatitis C. J Coll Physicians Surg Pak 2006;16:460-3. PMID:16827956        [ Links ]

53. Sarwar STS. Treatment failure in chronic hepatitis C: predictors other than viral kinetics. Rawal Med J 2010;35:217-20.         [ Links ]

54. Schiavon LL, Narciso-Schiavon JL, Carvalho-Filho RJ, Sampaio JP, El Batah PN, Silva GA et al. Evidence of a significant role for fast-mediated apoptosis in HCV clearance during pegylated interferon plus ribavirin combination therapy. Antivir Ther 2011;16:291-8. doi:10.3851/IMP1768 PMID:21555811        [ Links ]

55. Shaker OG, Eskander EF, Yahya SM, Mohamed MS, Abd-Rabou AA. Genetic variation in BCL-2 and response to interferon in hepatitis C virus type 4 patients. Clin Chim Acta 2011;412:593-8. doi:10.1016/j.cca.2010.12.009 PMID:21159314        [ Links ]

56. Shen C, Hu T, Shen L, Gao L, Xie W, Zhang J. Mutations in ISDR of NS5A gene influence interferon efficacy in Chinese patients with chronic hepatitis C virus genotype 1b infection. J Gastroenterol Hepatol 2007;22:1898-903. doi:10.1111/j.1440-1746.2006.04566.x PMID:17914967        [ Links ]

57. Sixtos-Alonso MS, Sanchez-Munoz F, Sanchez-Avila JF, Martinez RA, Dominguez Lopez A, Vargas Vorackova F et al. IFN-stimulated gene expression is a useful potential molecular marker of response to antiviral treatment with Peg-IFNalpha 2b and ribavirin in patients with hepatitis C virus genotype 1. Arch Med Res 2011;42:28-33. doi:10.1016/j.arcmed.2011.01.001 PMID:21376259        [ Links ]

58. Sood A, Midha V, Sood N, Awasthi G. Chronic hepatitis C - treatment results in northern India. Trop Gastroenterol 2002;23:172-5. PMID:12833703        [ Links ]

59. Stefano JT, Correa-Giannella ML, Ribeiro CM, Alves VA, Massarollo PC, Machado MC et al. Increased hepatic expression of insulin-like growth factor-I receptor in chronic hepatitis C. World J Gastroenterol 2006;12:3821-8. PMID:16804965        [ Links ]

60. Suresh RL, Kananathan R, Merican I. Chronic hepatitis C - a study of 105 cases between 1990-2000. Med J Malaysia 2001;56:243-7. PMID:11771088        [ Links ]

61. Szanto P, Grigorescu M, Dumitru I, Serban A. Steatosis in hepatitis C virus infection. Response to anti-viral therapy. J Gastrointestin Liver Dis 2006;15:117-24. PMID:16802005        [ Links ]

62. Zuberi BF, Zuberi FF, Memon SA, Qureshi MH, Ali SZ, Afsar S. Sustained virological response based on rapid virological response in genotype-3 chronic hepatitis C treated with standard interferon in the Pakistani population. World J Gastroenterol 2008;14:2218-21. doi:10.3748/wjg.14.2218 PMID:18407597        [ Links ]

63. Carneiro MV, Souza FF, Teixeira AC, Figueiredo JF, Villanova MG, Secaf M et al. The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol 2010;22:1204-10. doi:10.1097/MEG.0b013e32833bec1e PMID:20555268        [ Links ]

64. Barone AA, Tosta RA, Tengan FM, Marins JH, Cavalheiro Nde P, Cardi BA. Are anti-interferon antibodies the cause of failure in chronic HCV hepatitis treatment? Braz J Infect Dis 2004;8:10-7. doi:10.1590/S1413-86702004000100002 PMID:15286876        [ Links ]

65. Carneiro VL, Lemaire DC, Bendicho MT, Souza SL, Cavalcante LN, Angelo AL et al. Natural killer cell receptor and HLA-C gene polymorphisms among patients with hepatitis C: a comparison between sustained virological responders and non-responders. Liver Int 2010;30:567-73. doi:10.1111/j.1478-3231.2010.02212.x PMID:20456039        [ Links ]

66. Kumar D, Malik A, Asim M, Chakravarti A, Das RH, Kar P. Response of combination therapy on viral load and disease severity in chronic hepatitis C. Dig Dis Sci 2008;53:1107-13. doi:10.1007/s10620-007-9960-8 PMID:17934834        [ Links ]

67. Vigani AG, Macedo de Oliveira A, Tozzo R, Pavan MH, Goncales ES, Fais V et al. The association of cryoglobulinaemia with sustained virological response in patients with chronic hepatitis C. J Viral Hepat 2011;18:e91-8. doi:10.1111/j.1365-2893.2010.01385.x PMID:20969676        [ Links ]

68. Villela-Nogueira CA, Perez RM, de Segadas Soares JA, Coelho HS. Gamma-glutamyl transferase (GGT) as an independent predictive factor of sustained virologic response in patients with hepatitis C treated with interferon-alpha and ribavirin. J Clin Gastroenterol 2005;39:728-30. doi:10.1097/01.mcg.0000174025.19214.32 PMID:16082285        [ Links ]

69. Parise ER, de Oliveira AC, Conceicao RD, Amaral AC, Leite K. Response to treatment with interferon-alpha and ribavirin in patients with chronic hepatitis C virus genotypes 2 and 3 depends on the degree of hepatic fibrosis. Braz J Infect Dis 2006;10:78-81. doi:10.1590/S1413-86702006000200002 PMID:16878256        [ Links ]

70. Cheinquer N, Cheinquer H, Wolff FH, Coelho-Borges S. Effect of sustained virologic response on the incidence of hepatocellular carcinoma in patients with HCV cirrhosis. Braz J Infect Dis 2010;14:457-61. doi:10.1590/S1413-86702010000500006 PMID:21221473        [ Links ]

71. Gupta R, Ramakrishna CH, Lakhtakia S, Tandan M, Banerjee R, Reddy DN. Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C. World J Gastroenterol 2006;12:5554-6. PMID:17006999        [ Links ]

72. Liao XW, Ling Y, Li XH, Han Y, Zhang SY, Gu LL et al. Association of genetic variation in IL28B with hepatitis C treatment-induced viral clearance in the Chinese Han population. Antivir Ther 2011;16:141-7. doi:10.3851/IMP1703 PMID:21447862        [ Links ]

73. Araújo ES, Dahari H, Neumann AU, de Paula Cavalheiro N, Melo CE, de Melo ES et al. Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients. J Viral Hepat 2011;18:e52-60. doi:10.1111/j.1365-2893.2010.01358.x PMID:20738775        [ Links ]

74. Aziz H, Gil ML, Waheed Y, Adeeb U, Raza A, Bilal I et al. Evaluation of prognostic factors for peg interferon alfa-2b plus ribavirin treatment on HCV infected patients in Pakistan. Infect Genet Evol 2011;11:640-5. doi:10.1016/j.meegid.2011.01.022 PMID:21316487        [ Links ]

75. Butt AS, Mumtaz K, Aqeel I, Shah HA, Hamid S, Jafri W. Sustained virological response to pegylated interferon and ribavirin in patients with genotype 3 HCV cirrhosis. Trop Gastroenterol 2009;30:207-12. PMID:20426280        [ Links ]

76. de Almeida PR, de Mattos AA, Amaral KM, Feltrin AA, Zamin P, Tovo CV et al. Treatment of hepatitis C with peginterferon and ribavirin in a public health program. Hepatogastroenterology 2009;56:223-6. PMID:19453062        [ Links ]

77. Esmat G, Fattah SA. Evaluation of a novel pegylated interferon alpha-2a (Reiferon Retard^®) in Egyptian patients with chronic hepatitis C - genotype 4. Digest Liver Dis Suppl 2009;;3:17-9.         [ Links ]

78. Gonçales FL Jr, Vigani A, Goncales N, Barone AA, Araujo E, Focaccia R et al. Weight-based combination therapy with peginterferon alpha-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C. Braz J Infect Dis 2006;10:311-6. PMID:17293917        [ Links ]

79. Males S, Gad RR, Esmat G, Abobakr H, Anwar M, Rekacewicz C et al. Serum alpha-foetoprotein level predicts treatment outcome in chronic hepatitis C. Antivir Ther 2007;12:797-803. PMID:17713163        [ Links ]

80. Narciso-Schiavon JL, Freire FC, Suarez MM, Ferrari MV, Scanhola GQ, de Lucca Schiavon L et al. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon? Eur J Gastroenterol Hepatol 2009;21:440-6. doi:10.1097/MEG.0b013e3283089392 PMID:19382301        [ Links ]

81. Narciso-Schiavon JL, de Lucca Schiavon L, Carvalho-Filho RJ, Sampaio JP, Batah PN, Barbosa DV et al. Gender influence on treatment of chronic hepatitis C genotype 1. Rev Soc Bras Med Trop 2010;43:217-23. doi:10.1590/S0037-86822010000300001 PMID:20563484        [ Links ]

82. Parise ER, de Oliveira AC, Ferraz ML, Pereira AB, Leite KR. Cryoglobulinemia in chronic hepatitis C: clinical aspects and response to treatment with interferon alpha and ribavirin. Rev Inst Med Trop Sao Paulo 2007;49:67-72. doi:10.1590/S0036-46652007000200001 PMID:17505661        [ Links ]

83. Pereira PS, Silva IS, Uehara SN, Emori CT, Lanzoni VP, Silva AE et al. Chronic hepatitis C: hepatic iron content does not correlate with response to antiviral therapy. Rev Inst Med Trop Sao Paulo 2009;51:331-6. PMID:20209268        [ Links ]

84. Ray G, Pal S, Nayyar I, Dey S. Efficacy and tolerability of pegylated interferon alpha 2b and ribavirin in chronic hepatitis C - a report from eastern India. Trop Gastroenterol 2007;28:109-12. PMID:18383998        [ Links ]

85. Rossignol JF, Elfert A, Keeffe EB. Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol 2010;44:504-9. PMID:20048684        [ Links ]

86. Silva GF, Polonio RJ, Pardini MI, Corvino SM, Henriques RM, Peres MN et al. Using pegylated interferon alfa-2b and ribavirin to treat chronic hepatitis patients infected with hepatitis C virus genotype 1: are nonresponders and relapsers different populations? Braz J Infect Dis 2007;11:554-60. doi:10.1590/S1413-86702007000600006 PMID:18327466        [ Links ]

87. Sood A, Midha V, Sood N, Bansal M. Pegylated interferon alfa 2b and oral ribavirin in patients with HCV-related cirrhosis. Indian J Gastroenterol 2006;25:283-5. PMID:17264426        [ Links ]

88. Taha AA, El-Ray A, El-Ghannam M, Mounir B. Efficacy and safety of a novel pegylated interferon alpha-2a in Egyptian patients with genotype 4 chronic hepatitis C. Can J Gastroenterol 2010;24:597-602. PMID:21037988        [ Links ]

89. Tohra SK, Taneja S, Ghosh S, Sharma BK, Duseja A, Dhiman RK et al. Prediction of sustained virological response to combination therapy with pegylated interferon alfa and ribavirin in patients with genotype 3 chronic hepatitis C. Dig Dis Sci 2011;56:2449-55. doi:10.1007/s10620-011-1770-3 PMID:21706207        [ Links ]

90. Lerias de Almeida PR, Alves de Mattos A, Valle Tovo C. Sustained virological response according to the type of early virological response in HCV and HCV/HIV. Ann Hepatol 2010;9:150-5. PMID:20526007        [ Links ]

91. Khattab M, Eslam M, Sharwae MA, Shatat M, Ali A, Hamdy L. Insulin resistance predicts rapid virologic response to peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients. Am J Gastroenterol 2010;105:1970-7. doi:10.1038/ajg.2010.110 PMID:20234345        [ Links ]

92. El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, Refai R et al. Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol 2009;81:1576-83. doi:10.1002/jmv.21570 PMID:19626613        [ Links ]

93. Bader el-Din NG, Abd el-Meguid M, Tabll AA, Anany MA, Esmat G, Zayed N et al. Human cytomegalovirus infection inhibits response of chronic hepatitis-C-virus-infected patients to interferon-based therapy. J Gastroenterol Hepatol 2011;26:55-62. doi:10.1111/j.1440-1746.2010.06319.x PMID:21175794        [ Links ]

94. Shaker O, Ahmed A, Doss W, Abdel-Hamid M. MxA expression as marker for assessing the therapeutic response in HCV genotype 4 Egyptian patients. J Viral Hepat 2010;17:794-9. doi:10.1111/j.1365-2893.2009.01241.x PMID:20002306        [ Links ]

95. Belhadj N, Houissa F, Elloumi H, Ouakaa A, Gargouri D, Romani M et al. Virological response of Tunisians patients treated by peginterferon plus ribavirin for chronic hepatitis C: a preliminary study. Tunis Med 2008;86:341-5. PMID:19476135        [ Links ]

96. Chuang JY, Yang SS, Lu YT, Hsieh YY, Chen CY, Chang SC et al. IL-10 promoter gene polymorphisms and sustained response to combination therapy in Taiwanese chronic hepatitis C patients. Dig Liver Dis 2009;41:424-30. doi:10.1016/j.dld.2008.09.017 PMID:19004675        [ Links ]

97. Gao DY, Zhang XX, Hou G, Jin GD, Deng Q, Kong XF et al. Assessment of specific antibodies to F protein in serum samples from Chinese hepatitis C patients treated with interferon plus ribavirin. J Clin Microbiol 2008;46:3746-51. doi:10.1128/JCM.00612-08 PMID:18832124        [ Links ]

98. Gheorghe L, Grigorescu M, Iacob S, Damian D, Gheorghe C, Iacob R et al. Effectiveness and tolerability of pegylated Interferon alpha-2a and ribavirin combination therapy in Romanian patients with chronic hepatitis C: from clinical trials to clinical practice. Rom J Gastroenterol 2005;14:109-15. PMID:15990928        [ Links ]

99. Gheorghe L, Iacob S, Grigorescu M, Sporea I, Sirli R, Damian D et al. High sustained virological response rate to combination therapy in genotype 1 patients with histologically mild hepatitis C. J Gastrointestin Liver Dis 2009;18:51-6. PMID:19337634        [ Links ]

100. Gheorghe L, Iacob S, Sporea I, Grigorescu M, Sirli R, Damian D et al. Efficacy, tolerability and predictive factors for early and sustained virologic response in patients treated with weight-based dosing regimen of PegIFN alpha-2b ribavirin in real-life healthcare setting. J Gastrointestin Liver Dis 2007;16:23-9. PMID:17410285        [ Links ]

101. Ibrahim M, Gomaa W, Ibrahim Y, El Hadad H, Shatat M, Aleem AA et al. Nitric oxide levels and sustained virological response to pegylated-interferon alpha2a plus ribavirin in chronic HCV genotype 4 hepatitis: a prospective study. J Gastrointestin Liver Dis 2010;19:387-92. PMID:21188329        [ Links ]

102. Jabbari H, Bayatian A, Sharifi AH, Zaer-Rezaee H, Fakharzadeh E, Asadi R et al. Safety and efficacy of locally manufactured pegylated interferon in hepatitis C patients. Arch Iran Med 2010;13:306-12. PMID:20597564        [ Links ]

103. Kumthip K, Pantip C, Chusri P, Thongsawat S, O'Brien A, Nelson KE et al. Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy. J Viral Hepat 2011;18:e117-25. doi:10.1111/j.1365-2893.2010.01379.x PMID:20955493        [ Links ]

104. Laufer N, Bolcic F, Rolon MJ, Martinez A, Reynoso R, Perez H et al. HCV RNA decline in the first 24 h exhibits high negative predictive value of sustained virologic response in HIV/HCV genotype 1 co-infected patients treated with peginterferon and ribavirin. Antiviral Res 2011;90:92-7. doi:10.1016/j.antiviral.2011.02.013 PMID:21376083        [ Links ]

105. Njouom R, Sartre MT, Timba I, Nerrienet E, Tchendjou P, Pasquier C et al. Efficacy and safety of peginterferon alpha-2a/ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C. J Med Virol 2008;80:2079-85. doi:10.1002/jmv.21319 PMID:19040282        [ Links ]

106. Ridruejo E, Adrover R, Cocozzella D, Fernandez N, Reggiardo MV. Efficacy, tolerability and safety in the treatment of chronic hepatitis C with combination of peg-interferon - ribavirin in daily practice. Ann Hepatol 2010;9:46-51. PMID:20308722        [ Links ]

107. Seow EL, Robert Ding PH. Pegylated interferon alfa-2b (peg-intron) plus ribavirin (rebetol) in the treatment of chronic hepatitis C: a local experience. Med J Malaysia 2005;60:637-41. PMID:16515116        [ Links ]

108. Sombie RBA, Somda S, Sangare L, Lompo O, Kabore Z, Tieno H et al. Chronic hepatitis C: epidemiology, diagnosis and treatment in Yalgado-Ouedraogo teaching hospital in Ouagadougou. J Afr Hepato Gastroenterol 2011;5:5-16.         [ Links ]

109. Sporea I, Sirli R, Curescu M, Gheorghe L, Popescu A, Bota S et al. Outcome of antiviral treatment in patients with chronic genotype 1 HCV hepatitis: a retrospective study in 507 patients. J Gastrointestin Liver Dis 2010;19:261-4. PMID:20922189        [ Links ]

110. Su WP,, Peng CY, Lai HC, Liao KF, Huang WH, Chuang PH et al. Persistent transaminase elevations in chronic hepatitis C patients with virological response during peginterferon and ribavirin therapy. Hepatogastroenterology 2009;56:798-801.         [ Links ]

111. Yu JW, Sun LJ, Zhao YH, Kang P, Gao J, Li SC. Analysis of the efficacy of treatment with peginterferon alpha-2a and ribavirin in patients coinfected with hepatitis B virus and hepatitis C virus. Liver Int 2009;29:1485-93. doi:10.1111/j.1478-3231.2009.02080.x PMID:19602134        [ Links ]

112. Yu JW, Wang GQ, Sun LJ, Li XG, Li SC. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin. J Gastroenterol Hepatol 2007;22:832-6. doi:10.1111/j.1440-1746.2007.04904.x PMID:17565637        [ Links ]

113. Zhou YQ, Wang XH, Hong GH, Zhu Y, Zhang XQ, Hu YJ et al. Twenty-four weeks of pegylated interferon plus ribavirin effectively treat patients with HCV genotype 6a. J Viral Hepat 2011;18:595-600. doi:10.1111/j.1365-2893.2010.01373.x PMID:21105968        [ Links ]

114. de Segadas-Soares JA, Villela-Nogueira CA, Perez RM, Nabuco LC, Brandao-Mello CE, Coelho HS. Is the rapid virologic response a positive predictive factor of sustained virologic response in all pretreatment status genotype 1 hepatitis C patients treated with peginterferon-alpha2b and ribavirin? J Clin Gastroenterol 2009;43:362-6. doi:10.1097/MCG.0b013e3181775e6a PMID:19077732        [ Links ]

115. Jovanović M, Jovanović B, Potic M, Konstantinović L, Vrbic M, Radovanovic-Dinic B et al. Characteristics of chronic hepatitis C among intravenous drug users: a comparative analysis. Bosn J Basic Med Sci 2010;10:153-7. PMID:20507297        [ Links ]

116. Awad T, Thorlund K, Hauser G, Stimac D, Mabrouk M, Gluud C. Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials. Hepatology 2010;51:1176-84. doi:10.1002/hep.23504 PMID:20187106        [ Links ]

117. Swan T. The hepatitis C treatment pipeline report. New York: Treatment Action Group; 2011. Available from: http://www.treatmentactiongroup.org/uploadedFiles/About/Publications/TAG_Publications/2011/HCV%20pipeline%202011%20final.pdf [accessed 12 January 2012]         [ Links ].

118. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009;9:153-61. doi:10.1016/S1473-3099(09)70041-6 PMID:19246019        [ Links ]

119. Hofmann WP, Zeuzem S. A new standard of care for the treatment of chronic HCV infection. Nat Rev Gastroenterol Hepatol 2011;8:257-64. PMID:21468124        [ Links ]

120. Opar A. Excitement grows for potential revolution in hepatitis C virus treatment. Nat Rev Drug Discov 2010;9:501-3. doi:10.1038/nrd3214 PMID:20592732        [ Links ]

Submitted: 7 October 2011
Revised version received: 28 December 2011
Accepted: 3 January 2012
Published online: 3 February 2012
Competing interests: None declared.

* Correspondence to Nathan Ford (e-mail: nathan.ford@msf.org).