A systematic review of treatment response rates in Pakistani hepatitis C virus patients; current prospects and future challenges.

BACKGROUND: The estimated hepatitis C virus (HCV) carriers are approximately 10 million in Pakistan which usually progresses to chronic hepatitis, with rare cases of spontaneous viral eradication. The present article reviews the treatment status of HCV infection in Pakistani population and various factors associated with the treatment response rates.
METHODS: Literature on anti-HCV therapy was searched in PubMed, Google Scholar and PakMediNet. Thirty three different studies representing different geographic regions of Pakistan published from 2002 to 2016 were included in the present review. Weighted mean, standard error estimates (SE) and standard deviation (SD) were determined for each population group.
RESULTS: Mean value for sustained virological response (SVR) for standard IFN plus ribavirin (RBV) combination therapy was 68.38% ± 14.13% (range 33.8%-87.10%; SE 3.08) and pegylated-IFN plus RBV combination therapy 64.38% ± 8.68% (range 55.0%-76.00%; SE 3.88). The lowest value for SVR has been reported to be 24.3% (for genotype 1; administering INF-α 2b 3MU 3 times/week and RBV 1000-1200 mg/day for 48 weeks) while highest of 87.5% (genotype 3a; INF-α 2a 3MU 3 times/week and RBV 1000-1200 mg/day for 24 weeks). The mean value for rapid virological response (RVR) was found to be 48.18% ± 29.20% (SE 9.73). As PEG-interferon and direct acting antivirals (DAAs) are relatively expensive, interferon-alfa (IFN-α) and RBV combination therapy have been used widely to treat HCV infected patients in Pakistan for the last one and half decade. On average, 2.45% of the patients discontinued treatment due to severe side effects.
CONCLUSION: We encourage further studies on understanding host and viral factors associated with specific focus on harder to treat viral variants (relapsers and nonresponders). These variants are currently rising in the country.

Introduction

Chronic infection with hepatitis C virus (HCV) symbolize an important healthcare problem and is estimated to cause infection in up to 170 to 200 million people throughout the world[ with approximately 10 million in Pakistan.[ INF are cytokines (glycoproteins) released by the cells during infections. Naturally, the presence of double-stranded viral RNA in infected cells activates type-I interferon (IFN)-α and β genes at transcription level.[ Almost all of these usually progresses to chronic hepatitis, with rare cases of spontaneous viral eradication.[ IFN-α therapy was approved for the treatment of HCV infection in 1991 which showed very low virological response rates of <20% sustained virological response (SVR). In 1998, a higher response rates were reported by the administration of ribavirin (RBV) in combination with INF. In 2001, the response rate to the antiviral therapy was further improved by the introduction of pegylated-IFN; a more stabilized drug.[

In Pakistan since the last about 2 decades, combination treatment with IFN-α and RBV continues to be used widely in routine practice in HCV infected patients.[ Frequency of HCV infection in Pakistani population is significantly higher as compared to the neighboring countries like Iran, India, Afghanistan, Myanmar and Nepal.[ Moreover, full length HCV (genotype 3a) isolate from Pakistan has been described to be genetically different from those (HCV-3a isolates) from the rest of the world.[ In addition, more recently emerging HCV variants has been reported in Pakistani patients in response to IFN plus RBV antiviral therapy.[ Nevertheless, studies on estimating treatment response rates to the antiviral therapy in Pakistani population are still not clear, as limited numbers of reports are available on this subject[ mostly targeting small population groups. Therefore, the present review was designed to assess the treatment response rates; factors influencing treatment response rates and side effects associated with the antiviral therapies in HCV infected Pakistani patients.

Methods

Literature search

Antiviral therapy response

For estimating the antiviral response rates in Pakistani HCV infected patients; articles were searched in PubMed, PakMediNet and Google Scholar by using keywords like; Treatment of HCV in Pakistan, HCV treatment response rates in Pakistan, HCV therapy in Pakistan, factors influencing treatment response rates, HCV infection in Pakistani population, emergence of resistance in HCV, HCV treatment, and ethnicity and supportive therapy for HCV patients (Fig. 1). A total of 33 studies published from 2002 to 2016 fulfilled the inclusion criteria and were included in the present review.

Figure 1

Study design.

Inclusion criteria

Inclusion criteria were designed to screen the irrelevant references or articles with the information not sufficient to be included in the present study. Studies full filling the following criteria were included:

Samples were collected from Pakistani individuals.

An obvious description of the methods of detection of HCV infection and treatment.

Information about the number of individuals studied and their residing area were reported.

Duration of the treatment was reported.

End of treatment response (ETR) was reported for the treated patients.

The following simple formulas were used to describe the data from different manuscript in a similar way:

Total Patients = No. of patients with ETR + No. of nonresponders

Total Patients = No. of patients with SVR + No. of relapsed patients + No. of nonresponders

All the articles with the incomplete information were excluded.

Studies describing side effects of anti-HCV therapy, factors influencing treatment response, treatment status in resistant HCV patients, and supportive therapies administered in Pakistani HCV infected patients were included to discuss the subject in detail.

Full text review of the selected articles

Two of the authors independently reviewed all the full-text articles obtained during the electronic search. Data from the eligible articles were extracted on the electronic spread-sheet. All the disagreements were discussed and were referred to a third reviewer for final decision. The data extracted from the selected studies include location of the population, number of individuals reported in the study, HCV genotype, type and duration of therapy, percentage of patients with SVR, % relapsers and percentage of nonresponders to therapy. The study was conducted using PRISMA statement as described previously by Moher et al.[ As the current manuscript is a review article, it does not require ethical approval from the institutional ethical committee. All the data have been obtained from the previously published articles and the concerned manuscripts are properly cited.

Statistical analysis

The data was analyzed by using SPSS software package (version 16.0). Statistical parameters like mean, standard deviation and standard error estimates (SE) were determined for the data reporting percent ETR, SVR, relapsers, and nonresponders to antiviral therapies. Paired sample t test was used to assess the association between the variables.

Results and discussion

Treatment response rates in Pakistani population

Figure 2 shows details about the total number of patients and %SVR rates in each individual study (further details of each study are included in Tables 1–3). We further calculated the mean percent values for ETR, SVR, relapsers and nonresponders. Twenty two different studies showed mean percent value for ETR (%ETR) of 76.21% ± 13.8% (SE 2.52).[ Mean value for SVR was 60.70% ± 17.55% (SE 3.51),[ while 25 different studies reported that 21.31% ± 11.33% (SE 2.26%) of the patients were found nonresponders to the antiviral therapy.[ The mean value for rapid virological response were found 48.18% ± 29.20 (SE 9.73)[ and treatment relapsers 14.21% ± 8.32% (SE 1.66).[ The minimum value for SVR has been reported to be 24.3% (for genotype 1) using INF-α 2b plus RBV combination therapy for 48 weeks[ which is in agreement with previously described reports describing.[

Figure 2

Illustration of total number of patients and % sustained virological response in each representative studies. The minimum numbers of patients (16) were studied by Khalid et al[ and maximum of 1000 patients have been studied by Ali and Irum.[ The corresponding %SVR rates have been plotted on y-axis. SVR = sustained virological response.

Table 1

Treatment response rates in Pakistani HCV population.

Table 3

Summary of the reports based on the type of antiviral therapy.

Treatment response rates in different genotypes

Ten studies report treatment response in patients infected with HCV-3a. The mean SVR value for this specific genotype is 65.093% ± 14.94% (SE 4.31).[ In nine studies genotype was not determined; mean SVR rates in these studies were 69.06% ± 17.15% (SE 5.17)[ (see Tables 1 and 2 for details). In 2 studies both genotype 1a and 3a patients were treated with IFN plus RBV therapy and SVR rates of 73.695% ± 1.41% (SE 0.995) is reported.[ Only 2 studies included all the different genotypes and reported average SVR rates of 57.51% ± 7.75 (SE 5.48).[ These results show that HCV response rates in Pakistani HCV patients is quite diverse depending on viral genotype.

Table 2

Retrospective studies describing treatment response rates to INF + RBV therapy in Pakistani HCV infected population.

The most prevalent HCV genotype in Pakistan is HCV-3a (>70%) followed by 3b (estimated 9%) and 1a (about 3%).[ A study involving genotype analysis in the decade 2000 to 2010 reported change in the prevalence pattern of different genotypes prevalent in the country.[ It is an established fact that the effectiveness of the INF and RBV combination therapy depends on the HCV genotype; toxicity associated with the treatment and parameters that effect treatment response. Paired sample t test revealed significant association (P < 0.005) between HCV-genotype and %SVR rates. In addition, significant association between therapy type and genotype (P = 0.011).

Treatment of HCV infected Pakistani population with other complications

In a study Pakistani patients with HCV associated hepatocellular carcinoma (HCC) were found with the lowest SVR rates of 0%.[ Another study from Pakistan[ reported that combination therapy (Pegylated INF-α 2a plus RBV for 48 weeks) failed to treat HCV/hepatitis B virus (HBV) coinfected patients as either both HCV and HBV or only HBV infection remained detected at the end of treatment. Abbas et al[ reported a very low SVR rates of 13.33% (INFα 3 MU 3 times per week plus RBV 200–1000 mg per day for 6–12 months) in patients with HCV related glomerulopathy and recommended that such patients should be treated with modified doses for longer durations to achieve high treatment response. However, data regarding HCV treatment response rates in the patients with other complication including coinfected with viruses like HBV, HDV and HIV is still limited.

Treatment of resistant HCV infection in Pakistani population

Patients nonresponders or relapsed to IFN based therapies has been reported difficult to treat as compared to treatment naive HCV infected individuals. Butt et al[ reported treatment response rates of 40% (6/15) in patients previously nonresponding to antiviral therapy and 52.6% (10/19) in relapsed Pakistani patients by the administration of peg-INF + RBV therapy. In another study, Khokhar et al[ found a 49 year old patient nonresponder to INF plus RBV combination therapy (for 48 weeks and additional 24 weeks) followed by RBV and peg-INF (of 80 mcg/week) therapy. High dose of peg-INF (120 mcg/week) combined with RBV therapy for 48 weeks which resulted in SVR in that patient. These results show that nonresponders and relapsed patients can be treated with a high peg-INF dose in combination with RBV however; such patients must be closely observed for adverse effects of the therapy.

Side effects of the therapies

Thirteen different studies[ reported an average of 2.45% Pakistani HCV-infected patients discontinued antiviral therapy due to severe side effects. Most important adverse effects that lead to treatment cessation are shown in Table 4. The most frequent side-effects of antiviral therapy were fever, anemia, vomiting, nausea, anorexia,[ musculoskeletal pain, headache, fatigue, insomnia[ however; the treatment was still well-tolerated by most of the patients.[ Ahmed and co-workers[ observed seizures in 0.16% (8/4913) of the patients receiving INF + RBV combination therapy. Shaikh et al[ reported neutropenia in 36% and thrombocytopenia in 28% patients receiving INF +RBV combination therapy. Aziz et al[ reported that the adverse effects were more severe in the first few weeks of the start of therapy and gradually decreased in intensity as the treatment proceeded. Idrees and Riazuddin[ reported that 3.75% patients with reduced hemoglobin levels, thrombocytopenia and leucopenia were treated with adjusted doses of INF and RBV. In another study, 7.6% (5/66) were found with adverse side-effects like myalgias, cytopenias and intense lethargy due to antiviral therapy and were treated with reduced doses of INF and RBV.[ Nadeem et al[ reported that none of the 107 patients in Rawalpindi discontinued treatment due to side effects. A high frequency of depression (24%–70%) has been reported in patients with HCV infection which varies during INF treatment (0%–82%) depending on the treatment criteria.[

Table 4

Proportion of the patients with treatment cessation due to severe side effects of INF + RBV combination therapy.

Aamir et al[ studied the cutaneous complications in Pakistani HCV infected population during INF and RBV combination therapy and reported that most (97%) of the patients were observed with cutaneous side effects like hair loss (64%), oral pigmentation (48%), generalized pigmentation (27%), trichomegaly (32%), synophyrs (30%), pruritus (23%), aphthous stomatitis (21%), melasma (18.4%), nail pigmentation (16.8%), urticaria (16.8%) and photosensitivity (3.4%). Although, these undesirable effects were not so severe to discontinue the antiviral therapy however, this information will help dermatologists and physicians to counsel patients during antiviral therapy.

Mahmood and Muhammad[ studied 400 patients with chronic hepatitis C and reported side effects of INF plus RBV therapy in these patients. The most frequent was hematological side effects reported in 92.5% patients, flu-like symptoms (91%), gastro-intestinal (88.5%), dermatological (81.5%), neuropsychiatric (71.25%), respiratory related side effects (14%), thyroid function abnormalities (4%), major depression (1%), and suicidal tendency (0.5%). In another study, Alam et al[ reported 2 patients with digital clubbing; an unusual side effect of INF-α therapy however, no other data supporting this hypothesis is available in literature.

Supportive therapies used in Pakistan

Wazir et al[ supplemented the INF plus RBV therapy with oral administration of Vitamin E (600 mg 2 times daily) and reported decreased progression of fibrosis in chronic HCV patients. To treat severe anemia caused by the INF+RBV combination therapy, Abbas et al[ observed that erythropoietin supportive therapy for short period was beneficial. The flu like symptoms exhibited as a result of the antiviral therapy have been treated with simple analgesics like paracetamol.[ Aziz et al[ recommended analgesics and antidepressants (after psychiatric consultation) in patients with severe side-effects. Granulocyte colony stimulating factor or erythropoietins were administered as supportive therapy to relief neutropenia and anemia resulting from antiviral therapy.[ Antiemetics, antiulcers, and blood transfusion can also be beneficial as supportive therapy for the continuation of the anti-HCV treatment to obtain better results.[

Treatment response rates and its association with geographic and ethnic differences

Significant correlation has been reported between ethnicity of the patient and treatment response rates to anti-HCV therapy.[ Maximum treatment response rates with >78% SVR has been reported in the HCV patients from Khyber Pakhtunkhwa; the north-west province of Pakistan.[ These results further suggest that treatment response rate in Pashtun ethnic group is higher significantly as compared to non-Pashtun HCV infected population. This difference in SVR rates could be due to the difference in host genetic factors.[ Percent SVR rates to Pegylated INF plus RBV therapy in HCV infected patients residing in Lahore, Punjab (the central Pakistan) has been reported 70%,[ 74.44% at Islamabad-Capital territory[ and 57.6% at Karachi-Sindh[ which shows that treatment response rates differs greatly with the geographical and ethnic groups. The difference in treatment response rates may be due to various host related factors, distribution of different HCV genotypes and quasispecies in different geographic regions of Pakistan.

Host genetic factors associated with HCV in Pakistan

Beside viral genotype, virological responses after standard treatment and several basic host related factors (gender, age, body mass index, degree of hepatic steatosis and fibrosis), genetic makeup of host also play vital role in disease development and determining proper treatment plans. There are number of host genetic factors like single-nucleotide polymorphisms of IFNs, interleukin (IL)28A gene, IL28B gene, IL29 gene, IFN-γ, Tumor necrosis factor-related apoptosis inducing ligand receptor 1, human leukocyte antigens class II genes, cytotoxic T lymphocyte antigen-4, IL-10, IL-18, Mannan binding lecithin, Transforming growth factor, low molecular mass polypeptides 7 and Oligoadenylate synthetase genes which regulates treatment response.[ A few studies published from Pakistan elaborate the importance of these single-nucleotide polymorphisms in treatment response and viral clearance (Table 5). Despite the current successes in genetics involving studies that are opening new era in the field of HCV infection, still there is significant gap for the applications of these discoveries into innovative clinical practices[ and development of a novel therapeutic strategies.[

Table 5

Summaries of the studies conducted on Host genetic factors associated with HCV infection in Pakistan.

Advances in Antiviral therapies and challenges for Pakistani patients

During the last decade, improvements in the understanding of the viral life cycle have resulted in development of direct-acting antivirals (DAAs) [reviewed by Dubuisson and Cosset[ and Scheel and Rice[ however, there are still many issues that are associated with HCV treatment. These barriers include high percentage of patients who are unaware of their infection, limited access to therapy, high cost, successful HCV treatment does not eliminate the HCC risk,[ genotypic efficacy and occasional occurrence of resistance-associated variants.[ The recent clinical licensing of DAAs enables viral cure. However, limited access to therapy and treatment failure in patient subgroups warrants a continuing effort to develop complementary antiviral strategies. Furthermore, once fibrosis is established, curing HCV infection does not eliminate the risk for HCC.[ It would be interesting to investigate the effectiveness of the recently developed antivirals in Pakistani HCV infected patients, in the current transition phase from IFN + RBV to DAA combinations. However, so far there is no published study in this direction.

Conclusions

IFN plus RBV combination therapy continues to be used in Pakistan to treat HCV infection. Recently, emerging HCV variants has been reported in Pakistani HCV patients administered with IFN plus RBV antiviral therapy. However, the pattern of emergence of the antiviral resistant HCV variants in the country is still not known. In the era of rapidly changing antiviral therapies; limited information is available from Pakistan about harder to treat viral variants arising in the country. In addition, there is no study that describes cell culture based HCV resistant mutation arising in Pakistan. The present article encourages further studies on understanding host and viral factors associated with HCV in Pakistan.