A subset of HIV-1 subtype C-infected individuals – Extended High Viremics – maintains high plasma HIV-1 RNA levels for an extended period of time, and was a primary focus of the current study. While the fact that few individuals may have high levels of HIV-1 RNA load for a long period of time has been well recognized, the actual proportion of Extended High Viremics (individuals with HIV-1 RNA load ≥ 100,000 (5.0 log10) copies/ml over 100 days p/s) in primary HIV-1 subtype C infection has hardly been anticipated. The main finding of this study is that one third of HIV-1 subtype C-infected individuals have HIV-1 RNA load 100,000 (5.0 log10) copies/ml and higher during the period 100–300 days p/s, and 19% of individuals maintain high levels of HIV-1 RNA load during the period 200–400 days p/s.
The current analysis was based on cumulative data from two primary HIV-1 subtype C infection cohorts from southern Africa where the epidemic is most severe. Despite a few predictable differences, the two analyzed cohorts demonstrated remarkable similarity in evolution of HIV-1 RNA load and CD4+ T cell counts over time. Merging data from the two cohorts solidified the results due to the increased sample size. A relatively large proportion of Extended High Viremics was not likely due to over-representation of symptomatic patients because identification and enrollment of study subjects were not based on symptoms in both cohorts. A comparative analysis of the two cohorts provided evidence that the observed pattern of Extended High Viremics is common in primary HIV-1 subtype C infection. A high proportion of HIV-1 subtype C-infected individuals with high levels of viral RNA load for extended periods of time could contribute disproportionately to the high prevalence of HIV infection in southern Africa. Such Extended High Viremics seem particularly appropriate for emphasis using interventions described as Treatment-for-Prevention.
The trajectories of CD4 decline among Extended High Viremics provide evidence that the majority of individuals with long-lasting high HIV-1 RNA load are likely to be fast progressors. As is evident from , a dramatic decline of CD4+ cells occurred in Extended High Viremics during the first year of HIV-1 subtype C infection. Such a predictable CD4 drop provides a rationale for initiation of early HAART in Extended High Viremics, and leaves little reason for waiting when individuals with high viral HIV-1 RNA load reach the threshold of CD4. The six-month interval of CD4 testing, which is common practice in many countries, may be inadequate for Extended High Viremics due to the fast decline of their CD4+ cell counts, potentially compromising their immune systems substantially. Therefore, public health strategies for initiation of HAART might differ between Extended High Viremics (e.g., the HIV-1 RNA load-based approach) and others (e.g., the currently used approach focusing on CD4 decline).
Although the reasons for maintenance of high viral load in the subset of studied populations are still unidentified, it is likely that viral replicative fitness upon transmission is the major factor contributing to the existence of Extended High Viremics. For example, HIV-1 transmission between genetically similar hosts might provide a favorable environment for advanced replication of the virus adapted to the previous host, which could result in high HIV-1 RNA levels for an extended period of time. To address this important issue, further dedicated studies are warranted.
A comprehensive analysis of immune responses in the context of host genetics and evolution of viral quasispecies may shed light on potential reason(s) for the existence of Extended High Viremics, and is likely to reveal the underlying mechanisms. To keep the study focused on Extended High Viremics, immunological analysis was not included in the scope of the current study, which is one of the study limitations.
It would be tempting to compare the Extended High Viremics infected with HIV-1 subtype C with the well-documented patterns during the early phase of HIV-1 subtype B infection. However, we prefer to avoid a direct comparison due to a lack of comparable data between the epidemics caused by subtypes B and C, which to some extent limits generalization of our findings, at least until similar analyses are performed by others. First, there are important differences between the modes of viral transmission (e.g., heterosexual adults vs. MSM). Second, there is a substantial diversity between the genetics of targeted populations that has been made even more apparent by recent GWAS studies. Third, HIV-1 subtype differences and viral evolution on the population level should be adequately adjusted by relevant host immune responses. It would be important to (re-)analyze the existing data from the early HIV-1 subtype B studies in the context of Extended High Viremics. In this study, we tried to avoid a simplified comparison between HIV-1 subtypes that could be misleading and/or erroneous without a bold and sophisticated approach.
Due to the nature of the analyzed cohorts, information regarding source partners was not available, creating another study limitation. It would be important to track the changes in viral replicative capacity upon transmission to a new host, and to address potential associations between viral replicative capacity and maintenance of high plasma HIV-1 RNA load for an extended period of time in future studies. The relatively short time of follow-up limited the study's ability to track the rate of disease outcomes.
The role of Extended High Viremics
in viral transmission is likely to be large, although the current study was not powered to address this question. Extended High Viremics
may fuel the HIV/AIDS epidemic. A strong association between levels of HIV-1 RNA load and viral transmission is evident from previous studies [16
]. Maintaining high viral load for an extended period of time increases the probability of HIV-1 transmission. Extended High Viremics
with unknown HIV status might represent the highest-risk group for viral transmission. Therefore, a public health strategy aiming at proactive HIV testing and identification of Extended High Viremics
could be a critical part of successful management of the HIV/AIDS epidemic. Introduction of routine plasma HIV-1 RNA testing can help to identify not only individuals with high viremia, but also can improve identification of HIV-infected subjects before seroconversion. The cost-effectiveness and logistical issues related to feasibility of routine viral load testing constitute critical topics that need to be resolved by modeling and translational research in future studies.
Extended High Viremics
might represent an appropriate target for studying interventions for developing preventive strategies aiming at control of the HIV/AIDS epidemic in communities. Assuming the disproportionate contribution of Extended High Viremics
to new HIV-1 transmissions, successful management of Extended High Viremics
could provide for a valid assessment of efficacy of a variety of behavioral and biomedical intervention studies. Focusing on a subset of Extended High Viremics
could help to modify the “Treatment-for-Prevention” approach, and make it more feasible for mitigating the HIV epidemic in appropriate communities [28