The prevalence
The prevalence of HBV-HIV Co-infection among HIV-infected patients was 71 cases (5.6%). This prevalence is similar to countries of low endemicity, such as Ethiopia ( 5.6%) [27]. In Southeast Asia, the prevalence of HBV-HIV Co-infection was estimated to be 10.4%, and our prevalence is lower when to compare to the specific neighboring country of such as Singapore with their prevalence is (7.7), Thailand (3.3 to 13%) and Indonesia (3.2-15.3%) [25, 28, 29]
The prevalence of HCV-HIV Coinfection in our study was 14.8, which quite similar to the prevalence in Southeast Asia at 15.2% [6]. Comparing to other nearby countries, we were higher than Cambodia (5.5%) Myanmar (5.3%), Thailand (5.1%), Singapore (7.7%), but lower compared to countries such as Vietnam (42.5%) and Indonesia (17.9%) [30]. Globally in the US, the prevalence rates of HCV-HIV Co-Infection were higher at 25-50% [31].
In comparing our study finding for both HBV-HIV and HCV-HIV Coinfection to the latest and nearest study at a tertiary hospital in Malaysia by (Akhtar, Khan, et al. 2016), their HBV-HIV Co-infection prevalence was 13%, and HCV-HIV Co-infection was at 18.4 % respectively which was higher than in our study. [21] This might be due to few reasons such for instance, our study was more population-based, which covers both primary care and tertiary care; thus, the burden of HIV Co-Infection was lesser compared to studying in tertiary care only. Comparing to Penang, their documented numbers of AIDS cases itself from 1986-2015 were higher at 1155 numbers of cases compared to Negeri Sembilan, which only has 1003 numbers of cases [32]. Generally, such HIV Co-Infection prevalence differences could be due to differences in geographic regions, HBV vaccination rates, predominant modes of transmission, and prevalence of HBV and HCV in the general population as what several studies reported in different parts of the world, [28, 33]
As for the frequency of multiple HIV-Coinfection, out of 238 HIV cases with Viral Hepatitis Co-Infection, the majority were HCV –HIV Co-Infected cases followed HBV-HIV Co-Infected cases while the least were Co-infected with HBV-HCV-HIV cases. This majority is similar when compared to a study in Vietnam by (Huy, Vernavong, et al. 2014) [34].This similar prevalence result was due to both Malaysia and Vietnam has high proportion of HCV cases from IVDU s by 59% and 89.5-98.5% respectively [20, 28]. Malaysia was also ranked as the third country with the highest HIV prevalence after Vietnam among the Western Pacific Region in 2017 [35].
Our finding was, in contrast, to study by Singapore and Gondar, where the majority were coinfected with HBV-HIV, followed by HCV-HIV, and the least were coinfected with all HBV-HCV-HIV Co-infection [25, 27]. In Singapore, the reduction in numbers of IVDUs was due to the government's aggressive campaign and strict penalty, which leads to a lack of drug supply. Subsequently, this reduces the prevalence of HCV-HIV Co-Infection in that country[36].
HBV-HIV Co-Infection
Gender is a significant factor associated with both HIV-Coinfection and contributor to both predictive modelling. Males' gender has 3.629 odds (95% CI: 1.303,10.106) getting HBV-HIV than female, and this is consistent with studies done at Southeast Asia, Singapore and Tertiary Hospital in Penang [6, 21, 25]. Female HBV carriers have lower viral loads than male carriers, and the prevalence of serum HBV surface antigen (HBsAg) has been reported higher in men than in women [37, 38]. Moreover, majority of those that had HBV-HIV Co-Infection in our study were homosexual (42%), and some studies claimed that multiple partners were more common among homosexual men and anal sex is usually more traumatic than vaginal intercourse, resulting in an increased risk of exposure to blood transmission of HBV disease [4, 39]
HBV-HIV Co-Infection patients that have CD4 <199 cells/mm3 prone by 2.278 odd to get HBV-HIV (95% CI: 1.288,4.028) compared to those with CD4 >350 cells/mm3 in which is consistent with the study finding by Chen et al. 2016 [29]. Co-infection of HIV and HBV can cause complex interactions because HIV impairs the cellular immunity, leading to increased replication of HBV, this increase in viral replication of HIV and HBV can further contribute to the impairment of the immune system [40]. In general, studies showed an association between lower baseline CD4 cell count and HBV co-infection [12, 27, 41, 42]. Most of our viral hepatitis-HIV Co-infection patient are males and generally, the CD4 level among male is lower than female due to the daily activities of men who spend more time to do hard work for an extended period as well as men also more prone to stress, and these may contribute for lower CD4 count. [27]
Our study showed that HIV patients have 1.825 times odds (95% CI: 1.109,3.003) to be diagnosed as having the HBV-HIV co-infection at primary care rather than in the hospital. This determinant is a good reflection of how our adequate primary care provides good accessible services for HIV patients to do screening for Viral Hepatitis disease. Most of our HBV-HIV infected patients were infected via sexual transmission, where 60% of the cases were diagnosed at Primary Care. Out of this, 48% of the cases were diagnosed at Klinik Kesihatan Seremban under the special program as Sexual Transmitted Infection (STI) friendly clinic. The formation of STI friendly clinic was an initiative started since January 2016 did help much in capturing the HBV-HIV co-infection cases, which mainly contributed by sexual transmission [43]. Few studies showed that screening activities at the STI clinic detected many HBV, HCV, and HIV cases, which warrants specific preventive action to be done there. [44]
More cases of HBV-HIV infection were detected in primary care also due to the availability and accessibility to the service subsequently after the initiative done by the Ministry of Health to decentralized HIV treatment to primary care since 23 years ago. Successively, more medical doctors and family health medicine specialists are more competent in handling HIV cases well even provides more personalized care at primary care level, and this attracted many vulnerable groups for HIV to come out for the screening test and treatment. Furthermore, a systematic study found that the aspect of health care most valued by HIV patients was healthcare, which provides easy access for appointments and experienced and interactive doctors. Thus, our decentralization of services to primary care is a good initiative. [45].
In contrast, in some studies, hepatitis co-infection was not associated with increased primary HIV care utilization. It was because they utilize other subspecialty services, such as gastroenterology or hepatology, and due to evolving guideline recommendations for less frequent monitoring for patients with well-controlled HIV disease.[46] The difference between their findings and our study is that Malaysia has a different and good primary care system with less referral to the specialty in the hospital due to the training that we have to our specialist in primary care [47]. In the future, we hope that with the availability of excellent services in our primary care, more primary prevention can be done, which subsequently reduces the burden of Viral Hepatitis-HIV Co-infection diseases as what it supposed to be.
Male gender, CD4 level less than 199 cells/mm3 and primary care type of facilities was the significant factor in the modeling to predict the outcome of HBV-HIV Co-Infection, and a focused targeted intervention strategy should be based on this. Thus, our recommendation of HBV revaccination should be made at primary care facilities to a mainly male patient with a low CD4 level than <199 as they are more prone to HBV-HIV. However, the patient's CD4 must be lifted to more than 350 cell/mm3 before the revaccination of Hepatitis B [22, 23, 48].
Hepatitis B revaccination has been recommended for MSM, IVDU, and heterosexuals with a recent history of a sexually transmitted disease or multiple sex partners by Europe Communicable Centre and many other countries [5, 49]. The recommendation for Hepatitis B revaccination for IVDU in the large scale HIV prevention program was also suggested to the countries that have a high HIV burden coming from IVDU key population. [34].
Since the type of facilities at primary care as one of the significantly associated determinants with HBV-HIV Co-infection, these facilities serve as a good avenue for the revaccination program and should be done for the targeted group mentioned above. The successful outcome of HIV infected patients will require not only appropriate antiretroviral and antiviral therapy, but also sustained attention to long-term treatment toxicities, non-HIV-specific comorbid conditions (e.g., substance abuse, psychiatric illness), and comorbid behaviors (e.g., adherence, diet, and exercise) [50]. Thus, a more holistic approach should be given to the high-risk group to prevent them from getting HBV-HIV Co-Infection at the primary care setting.
HCV-HIV Co-infection
As for HCV-HIV Co-Infection patients, males have 7.725 odds (95%CI: 2.982, 20.013) of getting the co-infection than females, which is consistent with the finding by study at Southeast Asian and study at a tertiary hospital in Penang [21, 29]. In HCV-HIV Co-Infection, the female genetics made them have a spontaneous clearance of the infection of HCV, and the female hormone of estrogen is protective for the liver from progress to chronic HIV [51, 52]. Besides, the majority of modes of transmission for HCV-HIV Co-Infection were IVDU (74%), and it was proven that most of the IVDU were men [30]. Even though only a small percentage of the cases in HCV-HIV is due to the homosexual transmission in our study (6%), they were still at a higher risk of contracting HCV-HIV Co-Infection due to the practice associated with mucosal trauma and recreational drug use [53]. Furthermore, one study also found that HCV-HIV coinfected men were more likely than HIV-uninfected men to shed HCV RNA in semen[54]
Malay has 4.098 times odd to get HCV-HIV (95%CI: 1.893,8.871) compared to Chinese, and this was consistent with the study finding at Singapore and Penang even though both studies have Chinese as most of their study population races. Generally in Malaysia, Malay constitute the majority of the sociodemographic by 61.7% followed by Chinese 20.8% and the majority of Malaysian IVDU by 2018 were Malay by 20,671 (80%) numbers followed by Chinese at 1480 (6%) in numbers [55], and this explained why in our population-based study, Malays were more prone for HCV-HIV Co-Infection.
IVDU has a higher odd of 5.916 to get HCV-HIV (95% CI 3.875,9.034) compared by sexual modes of transmission. These odds were higher when comparing to the nearest local study by Akhtar, Khan, et al. 2016, which found that IVDUs have 2.376 odds (95%CI: 1.541,3.664) to get the HCV-HIV Co-Infection. Globally, our finding is consistent with the finding by Choy, Ang et al. 2019 and Chen et al. 2016 and, where IVDUs have 10.15 to 34 times odds for HCV-HIV Co-Infection [6, 21, 25]. Sharing needle is acknowledged as the main route of HCV acquisition among IVDU from the direct percutaneous exposure to contaminated blood from a needle, and this risk also depends on the quantity of blood inoculated and the viral load of that person has.[24] The risk is higher in people with HIV infection, thus made them highly infectious. [56]
High-risk screening programs in prison and methadone have 4.312 odds (95%CI: 1.571,11.838) in detecting the HCV-HIV Co-Infection than usual population screening. Among the HCV-HIV positive patient from the high-risk screening program,79% were from the prison screening program, whereas another 21% were from the methadone screening program. Screening of HIV program in Malaysian prison was started since 1990, with the latest guideline in 2002 which suggest screening of HIV on entrance into the prison, followed by 3 or 6 months before discharged without no screening in during the imprisonment. Once the patient detected HIV positive, they will be referred to the nearest hospital were at the same time will be screened for HCV and HBV, followed by treatment if indicated.[57]
High-case detection in prison was that prisoners often come from vulnerable strata of society suffering from poor health with few health opportunities. Besides, they also have a high probability of engaging in injecting drug practice and sexual risk behaviors even before the incarceration [58]. When in imprisonment, these concentrations of individuals coming from high-risk environments may remain their high-risk behaviors even in the correctional institute, making it a critical setting for transmission of HCV infection [59].A study by (Treloar, McCredie, et al. 2015) suggested that the potential for transmission of hepatitis C virus (HCV) in prison settings was well established and directly associated with the sharing of injecting and tattooing equipment, as well as physical violence.[60]
Even though in our study we cannot determine the exact onset of the HCV-HIV infection occurred either before imprisonment or during the imprisonment, the above evidence showed that HCV-HIV infection could occur at both stages along with the evidence that the Malaysian recidivism rate is 16.7% from all the prisoners.[61]
Male, Malay, IVDU risk factor, and high screening source of cases are significant factor in the modeling to predict the outcome of HCV-HIV infection. Since the Hepatitis C treatment has been decentralized to primary care, we expect the reinfection can occur if this high-risk behavior continues. Evidence suggested that high rates of HCV reinfection after spontaneous clearance or treatment in HIV positive MSM even more higher than IVDU thus targeted intervention in both group should be emphasized [24, 62]
A more targeted and outreach approaches are also needed for IVDU and MSM because stigmatization limits their access to testing and treatment [30]. Studies suggested that guideline of screening and access to testing and treatment was challenging and poorly implemented primarily in a low-income country and middle-income setting as well in the population such IVDU, prisoners, site worker and MSM [63, 64]. Thus, a proper counseling and strategies should be given along with a more frequent screening of HCV during pre and post HCV treatment for them especially IVDU from the prison. The prevention of the Hepatitis C program at prison should be done , including yearly voluntary and compulsory testing instead of testing during the enrollment and before release from prison only [5, 65]. The positive HCV-HIV patients are encouraged to be treated while in the prison program, as it was suggested to be more efficient [66].