Late HIV presentation to care: Earlier HIV diagnosis in Primary Health Care & Long-term survival & Tuberculosis co-infection

Delay in HIV diagnosis carries important consequences for both the individual and society. While there is an encouraging decreasing trend in the global HIV incidence, late HIV diagnosis remains a blot in the management of HIV, with still half of new HIV patients presenting at late stages of the disease at the time of diagnosis. Despite public health efforts, the magnitude of late HIV diagnosis has remained unchanged over the last decade. Late HIV diagnosis leads to increased morbidity and mortality, lower life quality, poorer immune reconstitution, persistent chronic inflammation, higher health care costs, and increased risk of onward transmission in the population before diagnosis. Individuals not belonging to the traditional HIV risk groups, such as heterosexual men, females, and older patients, as well as non-European individuals, are at a higher risk of late HIV diagnosis. The first group is primarily attributable to physicians’ (and patients’) low clinical suspicion of undiagnosed HIV, but the latter is counterintuitive given that many individuals from non-European countries come from HIV-endemic areas.

Various guidelines have been developed to better target patients for HIV testing. The European guidelines recommend routine HIV screening in pregnant women and targeted HIV testing in high-risk groups for HIV acquisition and in case of presenting to care with an HIV indicator condition. Despite these recommendations, many patients are not offered an HIV test in the latter two situations, so-called missed opportunities for earlier HIV diagnosis. These missed opportunities are frequent, and some studies have reported figures as high as 70-80% of newly diagnosed PLWH having had at least one missed opportunity for earlier HIV diagnosis. Primary health care (PHC) serves as the frontline service and is pivotal in facilitating early HIV diagnosis through provider-initiated HIV testing. Thus, engaging PHC could improve timely HIV diagnosis and, ultimately, HIV prognosis.

In the studies included in this thesis, we investigated behavioural aspects and risk factors related to PHC associated with HIV infection to improve the effectiveness of HIV testing strategies. For those PLWH where “the damage had already occurred” and were unfortunately diagnosed at a late stage of the infection, we evaluated determinants for long-term survival and incomplete immune recovery. Finally, we assessed TB risk and associated mortality in PLWH as TB is still one of the most common AIDS-defining opportunistic infections worldwide in late HIV presenters.

Studies I and II were designed as matched case-control studies. From the Danish HIV Cohort, we included all adult PLWH diagnosed with HIV between 1998-2015 and living in Denmark for ≥3 years at HIV diagnosis. From the population, we included age- and gender-matched controls (13:1). In total 2784 HIV cases and 36,192 population controls were included in the analysis. We found that PLWH frequently attended PHC in the three years preceding HIV diagnosis. Actually, 93% of PLWH had attended PHC at least once in this period, with a median number of visits of 14. Only 4% and 13% of Danish-born and non-Danish-born men and 3% and 26% of Danish-born and non-Danish-born women had had no contact with PHC in the previous three years of HIV diagnosis. Besides, we observed that PLWH had a higher prescription of antimicrobials compared to controls in the 3 years before HIV diagnosis. The antimicrobial drug prescription of any of the antimicrobial drug classes included in the study was associated with the risk of subsequent HIV diagnosis. This association was higher with higher levels of antimicrobial consumption. Although we did not dispose of indication information for the prescriptions, we assume that the use of antimicrobial drugs was in many cases a surrogate marker for missed HIV indicator conditions (e.g., community-acquired pneumonia, STIs, herpes zoster, or candidiasis).

Study III was designed as a cohort study. From the Catalan HIV PISCIS cohort, we included all adult PLWH initiating ART between 2005-2019, who were alive 2 years after, with available CD4 cell count at ART initiation and two years after (n=2719). We found that despite the late HIV diagnosis, 44% of 2-year 11 survivors’ late presenters achieved a CD4 cell count > 500cells/µL after ART initiation. Two-year CD4 count recovery was a strong independent early predictor for long-term all-cause mortality, independently of the CD4 cell count at ART initiation. Importantly, late HIV presenters with two-year CD4 count >500 cells/µL had similar survival to non-late presenters. Furthermore, initiating ART with an integrase-inhibitor (INSTI)- based regimen in the first two years was associated with a significantly better two-year immune recovery and better long-term survival.

Study IV was designed as a nationwide population-based cohort study. We included 6982 PLWH followedfor-HIV-care in Denmark between 1995-2017. Overall, 217 develop TB in the study period. Two different populations of HIV/TB coinfected individuals were identified: those presenting to care with concomitant HIV/TB infection (more frequently migrants, late presenters with a higher percentage of disseminated TB) and those diagnosed with TB >3 months from HIV diagnosis (median time from HIV diagnosis to TB 5.1 years (IQR 2.0-9.6), more frequently Danish-born individuals, with a higher social burden, higher rates of liver and non-TB AIDS-related comorbidities, a higher percentage of pulmonary TB and with a higher risk of suboptimal linkage to care). The latter had a worse TB outcome, with higher rates of treatment discontinuation and death. The incidence of concomitant HIV/TB coinfection remained high and unchanged over the study period, while the incidence of TB diagnosed >3 months after HIV diagnosis, declined over time, probably related to better ART, ART coverage, and earlier ART initiation. The risk of TB also declined with time from HIV diagnosis and with CD4 immune recovery. No individual had received treatment for latent TB infection (LTBI). Migration, history of IDU, not receiving ART, and HIV-induced immune suppression were identified as risk factors for developing TB. The overall mortality rate in PLWH co-infected with TB remained high over time and HIV-associated immunosuppression, disseminated TB, and social burden were found to be significant predictors of death in these patients.

Taken together, the loss of diagnostic opportunities for HIV diagnosis represents a critical turning point to further curb the HIV epidemic globally and improve HIV prognosis. PHC is frequently attended by individuals with undiagnosed HIV infection and should provide numerous opportunities for HIV testing. There is thus a need for more proactive testing in PHC, implementing existing HIV testing guidelines and other novel strategies. Some particular antimicrobial consumption is associated with a higher subsequent risk of HIV diagnosis and could be used as a marker to prompt proactive testing of HIV infection. Using electronic health record alerts, this strategy could be easily implemented in PHC helping reduce counselling time and contributing to the normalization of HIV testing and the reduction of HIV-related stigma. In LP, two-year CD4 cell recovery is a good early predictor of long-term survival, much more precise than initial baseline CD4 cell counts, and this parameter could be used in routine clinical practice to early orient the patient’s clinical trajectory. Furthermore, our findings support the positioning of INSTI-based ART as preferred regimens. INSTI were associated with a significantly better two-year immune recovery and, importantly, better outcomes including long-term survival in LP, though additional research is required to confirm our findings.
Finally, we found that TB rates in PLWH decreased over time and paralleled CD4 cell recovery, which emphasizes the importance of early HIV diagnosis and successful ART. Due to the continually high incidence of late HIV presentation with concomitant TB, more proactive HIV testing, and TB prevention measures are required. Migration, IDU, and HIV-induced immunosuppression have all been identified as important risk factors for TB and underline the importance of routine screening and treatment of LTBI in these high-risk groups in low-TB incidence countries.