CLINICAL HIV AND AIDS JOURNAL (ISSN:2633-5476)

Background: From a relatively slow-rising epidemic, HIV has accelerated its pace in the Philippines since 2007. This study analyzed the epidemiology, clinical profile, and factors affecting the disease outcome of Filipinos infected with HIV seen at the Research Institute for Tropical Medicine (RITM).

Methods: Patients aged >18 years with confirmed HIV infection and entered to care at RITM from 1989 to July 2015 were included in the analysis. Clinical and laboratory profiles were reviewed. The factors associated with AIDS-defining conditions or HIV-associated mortality (as a combined outcome) and HIV-associated mortality alone were evaluated using competing risk regression.

Results: Of 4,942 patients included in the study, majority were men who have sex with men, local workers, with a median age of 35 years (IQR 29.90-41.78) and CRF01_AE as the common HIV subtype. Incidence rate of AIDS-defining condition or HIV-associated mortality (as a combined outcome) was 8.47 per 100 patient-years (95% confidence interval [CI] 7.88-9.120) and the incidence rate of HIV-associated mortality was 3.35 per 100 patient-years (95% CI: 3.01-3.74). Educational attainment, migrant work, heterosexual exposure, tuberculosis and other opportunistic infections, low CD4 cell count, anemia and patients not on antiretroviral therapy were significantly associated with the risks of having the study outcomes.

Conclusion: The epidemiologies of patients with HIV have changed over time but the efficacy of ART remained. Late presentation in clinical care is significant predictor of poor outcome hence the need to scale up HIV testing for early HIV diagnosis. A holistic approach to care is important.

HIV; AIDS; Antiretroviral therapy; CD4 cell

It was in 1984 when the first case of HIV was reported in the Philippines. Previously HIV was relatively slow rising epidemic. By 2007, however, the HIV epidemic has rapidly accelerated it space. It took ten years for the number of new HIV cases to double from 154 cases in 1996 to 309 cases in 2006 and merely two years for the 342 new HIV cases in 2007 to increase almost a hundred fold to 629 new HIV cases in 2009. There was also a marked a shift in the demographic of patients who were acquiring the infection. The combined number of those infected through homosexual and bisexual contact has continually exceeded the number of cases that were infected through heterosexual contact. Whereas overseas Filipino workers (OFW), who presumably acquire the infection outside the country, used to comprise majority of newly diagnosed cases, recent report showed they merely comprised 11% of new cases [1].

Antiretroviral therapy (ART) became universally accessible in the country by 2006. From over a hundred patients on treatment, it increased to 12,533 by end of 2015 [2] and to 24,754 patients by end of 2017 [3].

In 1989, through a grant from the Japan Foundation for AIDS Prevention (JFAP), the Research Institute for Tropical Medicine (RITM) started a cohort study on the natural history of HIV among Filipinos. This cohort study eventually evolved into a research-based clinical services and setting the standard of care for HIV in the country. The cohort, continued to be a rich source of demographic, clinical and laboratory data that help inform national guidelines and policies for HIV and AIDS treatment and control.

Study population and outcome definition

Since 1989, medical records of patients with HIV seen at RITM utilized clinical research forms (CRFs). Electronic copies of these CRFs were made for each clinic visits. Anonymized and de-identified data were extracted and analyzed from the electronic files.

All patients 18 years old and above with confirmed HIV infection who entered into care at RITM from 1989 to July 2015 and with at least one prospective follow up were included in the analysis. The two outcome variables were occurrence of AIDS-defining condition or HIV-related mortality (as a combined outcome) -patients were considered to have this outcome if he/she developed AIDS-defining conditions or died due to HIV-associated illness. If the patient developed both of these events eventually across the duration of the study, the earliest event, which took place, was taken as the final outcome. 

HIV-related mortality- defined as death related to HIV. Censored observations were considered as those individuals that did not experience or develop the outcome of interest after entry into care up until July 2015. Loss to follow-up (LTFU) was defined as no clinic visit within 24 months prior to the last RITM database closed date (July 2015), not including transferred cases. Death not associated with HIV was accounted as competing risk.

Definition of variable of interest

Baseline CD4 count, viral load (VL) and hemoglobin level were defined as the closest measurements within the defined window period of 6 months prior to entry into care and 1 month after entry into care. Patients were considered hepatitis B co-infected if they had any record of a positive hepatitis B surface antigen test in the database. Prior AIDS-defining condition at baseline were defined as having a Center for Disease Control and Prevention (CDC) category C illness at any time prior and 1 month after entry into care [4].

Statistical analysis

To explore the factors associated with the two outcome of interest: 1) AIDS-defining illness and/or HIV-associated mortality and 2) HIVassociated mortality, we used competing risk regression analysis. Covariates included age, sex, education, occupation, mode of HIV exposure, number of sexual partners, HBV status, prior CDC category C illnesses, prior opportunistic infections, baseline hemoglobin level, CD4 count and viral load and antiretroviral therapy.

Predictors to be included in the multivariate model were selected based on a significance level of ≤ 0.10 in the univariate analysis. Predictors were retained in the multivariate model if one or more categories exhibited a p-value ≤ 0.05. Patient with missing data were included in the analyses but hazard ratios for missing categories are not reported. 

All data management and analysis were performed using Stata software version 13.1 (Stata Corp., College Station, TX, USA).

Demographic characteristics

Of the 5,474 patients with demographic data enrolled at RITM, 4,942 (90.2%) met the inclusion criteria for a total of 8,460 follow up years. Although majority of the patients were male, the difference became more apparent starting 2007 where male comprised 97% compared to 68.85% prior to 2007. Patients were younger upon entry into care starting 2007 compared to previous years median age 35.29 Inter quartile range (IQR 29.90-41.78) versus 28.19 (IQR 25.12-32.32) (p=<0.0001). There were significantly fewer overseas workers, more patients with higher educational attainment and reporting either homosexual or bisexual behaviors starting 2007compared to previous years. Although majority of patients who entered onto care prior to 2007 had no available CD4 test data, most patients in both eras had very low baseline CD4 cell count (Table 1).

Clinical profile

Majority of patients had no opportunistic infection upon entry into care. The most common presenting illnesses were tuberculosis (9.2%) and Pneumocystis jirovecii pneumonia (2.4%). Among those with hepatitis B screening, only about 7% were reactive to HBs antigen test. The median CD4 cell count was 273 cells/mm³ (IQR 71-375) and median hemoglobin level was 14.1 g/dl (IQR 12.9-15.3) among those on ART, 68.5% were on non-nucleoside reverse transcriptase (NNRTI)-based regimen. Only 2.7% of patients had viral load testing before ART initiation (Table 2).

HIV Subtype

Among patients with HIV subtype information, 71.33% was CRF01_AE and 23.43% were subtype B. Subtype B was the predominant subtype prior to 2008 and the frequency of CRF01_AE started to increase in the succeeding years (Table 2 and Figure 1).

Clinical outcome

Among the 4,942, 717 (14.5%) patients developed new AIDSdefining condition or HIV associated mortality (as a combined outcome), giving an incidence rate of 8.47 per 100 patient years (95% confidence interval [CI] 7.88-9.12). The rate of lost to follow-up (LTFU) was 2.7 (95% CI: 2.39-3.11) per 100 patientyears.

Meanwhile, HIV-associated mortality occurred in 326 patients (6.6%) at an incidence rate of 3.35 per 100 patient years (95% CI: 3.01-3.74).    

Low level of education, overseas worker, heterosexual exposure, TB and other OIs, low CD4 cell count, low hemoglobin level and not being on ART were all significantly associated with both combined outcomes and HIV-associated mortality (Tables 3 & 4).

The cumulative probability of progressing to AIDS or death and mortality were significantly increased among heterosexual males and overseas workers (Supplemental Figures 1 & 2). 

We reported the outcome of the biggest and longest running cohort of patients with HIV in the Philippines. Although ART became universally available in the country since 2006, this is the first study that provided evidence based on largest database of patients with regard to the efficacy of ART in reducing HIV related morbidity and mortality (1.188 per 100 patient year, CI .96-1.47 vs. 15.1 per 100 patient year, CI 13.19-17.27). Similar to other cohort studies from various regions in the world, our study showed not only the benefit of ART [7-10] but it also demonstrated that advanced HIV disease, as evidenced by low CD4 count, presence of AIDS defining illness and low hemoglobin count could adversely affect outcome [11-16].

We were also able to document the shift in the demographic of the HIV epidemic in the country overtime. In the past decade we observed that the transmission was predominantly local and driven by men who have sex with men (MSM). Although HIV was initially identified among gay men in the early 80’s, a global re-emergence of MSM driven HIV was observed beginning early part of year 2000 [17,18].

Although the requirement for HIV testing for OFW remains, the number of new infections in this population continues to decline. This is the result of the regular pre-departure seminars provided by hiring companies, government agencies and nongovernment organizations. The increasing frequency of CRF01_AE, the predominant subtype in Southeast Asia, is consistent with local HIV transmission [19,20]. A phylogenetic study is underway to determine possible timeline ofCRF01_01 introduction in the country and relationship to circulating strain in the region.

We reported better outcome among homosexual males patients. This was similar to the findings of Zhou et al. in 2005 [16] and Garriga et al. in 2015 [13] although the study of Coelho et al. in 2016 [10] did not show similar result. Most OFWs were heterosexual male seafarers. Access to ART and other medical services would be more difficult while in foreign country or on board a vessel for overseas workers in general. Some men who self-reported as heterosexuals maybe closeted gay men and fear of discrimination could have adversely affected their health seeking behavior and adherence to medication. Homosexual males who have no issues regarding gender identity may be more comfortable in seeking information and assessing care and have better social support system.

There has been concern regarding response to ART among patients with CRF01_AE, the predominant subtype in Southeast Asia since efficacy trials were conducted in predominantly subtype B western countries. Our study and other cohorts in the region have demonstrated efficacy of ART comparable to the western countries [16].

Although our data came from the biggest real world clinical cohort in the Philippines, being a retrospective and purely observational study, there were many missing variables. Almost one third of patients had no viral hepatitis B screening. HIV viral load testing prior to ART is not part of local treatment guideline; hence, this information was not available in 97% of patients.

We showed that CRF01_AE has become the predominant subtype in the recent years. With few patients with HIV subtype data and majority of patients were MSM, we could not generalize this trend for the whole country nor to other key affected population.

In summary we have shown how the demographic and molecular epidemiology of HIV changed over time. We also demonstrated the efficacy of ART for our patients. Late presentation in clinical care is a very significant predictor of poor outcome hence the need to scale up HIV testing for early HIV diagnosis. A holistic approach to care that would address the social and psycho emotional needs of patients is important. A care plan including identifying clinic, support group or mechanism to access ART for overseas worker must be in place as well as support for men who have issues regarding sexuality and disclosure.

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