HIV-1 subtype C-infected individuals maintaining high viral load as potential targets for the "test-and-treat" approach to reduce HIV transmission

Abstract

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1-4.2 log(10)) and cART-initiating cohorts (5.1-5.3 log(10)) by about one log(10). The proportion of individuals with high (> or = 50,000 (4.7 log(10)) copies/ml) HIV-1 RNA levels ranged from 24%-28% in the general HIV-positive population cohorts to 65%-83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%-50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load > or = 50,000 (4.7 log(10)) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%-82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified "test-and-treat" strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.

Figure 1. HIV-1 subtype C RNA levels in seven BHP cohorts (pre-cART baseline data).

In the box plots, the boundary of the box closest to zero indicates the 25^th percentile, a black line within the box marks the median, a red line within the box marks the mean, and the boundary of the box farthest from zero indicates the 75^th percentile. Whiskers above and below the box indicate the 10^th and 90^th percentiles. Points above and below the whiskers indicate outliers outside the 10^th and 90^th percentiles. Text above each box plot indicates the BHP study number and the name of the corresponding cohort. Numbers of included participants per cohort are shown at the bottom within the graph. Median, IQR, mean, and 95% CI are presented at the bottom outside the graph.

Figure 2. Distribution of HIV-1 RNA levels in seven BHP cohorts (pre-cART baseline data).

Y-axis shows the count, and differs between cohorts. X-axis denotes log₁₀ HIV-1 RNA levels; the scale is uniform for all cohorts. Labels in each graph indicate the BHP study number and the name of the corresponding cohort.

Figure 3. Gender differences in HIV-1 RNA levels in four BHP cohorts (pre-cART baseline data).

For explanation of box plots see Figure 1 legend. Text above each box plot indicates the BHP study number and the name of the corresponding cohort. Comparison of HIV-1 RNA levels between genders was performed by the Mann-Whitney Rank Sum test, and p-values are presented above the box plots. Numbers of included male (M) and female (F) participants per cohort are shown at the bottom within the graph. Median and IQR are presented at the bottom outside the graph.

Figure 4. Dynamics of HIV-1 RNA levels in subjects with high early viral set point, n = 14.

High HIV RNA level was considered at ≥50,000 (4.7 log₁₀) copies/ml. Early viral set point was determined as a mean value from 50 to 200 days p/s. Data for each subject is presented in a separate graph. Patient code is shown at the top left of each graph. Y-axis shows HIV-1 RNA levels, log₁₀ copies/ml; scale is uniform for all subjects; the 50,000 (4.7 log₁₀) copy threshold is shown as a dashed line. X-axis denotes days from estimated seroconversion; scale differs between subjects due to differences in the follow-up period. Filled circles delineate pre-cART HIV-1 RNA values, and open circles show post-cART HIV-1 RNA values. Time of cART is highlighted by gray zone, if applicable. For calculation of slopes and prediction of time of decline to the threshold of 50,000 (4.7 log₁₀) copies, only pre-cART data were used. The conservative estimate of individual time to decline below 50,000 (4.7 log₁₀) copies is shown under the patient code with the less conservative Kaplan-Meier estimate in brackets (if it differs from the conservative estimate).

Figure 5. Identification of high HIV-1 RNA individuals by repeated HIV testing: six-month intervals vs. twelve-month intervals.

All subjects are assumed to be HIV-seronegative at initial HIV testing, and to acquire HIV-1 infection shortly after that. The study subjects' code is shown at the left of the graph, and four acutely infected individuals are highlighted. The high viral load for each subject is presented as a shaded triangle symbolizing the “tip of the viral load iceberg”. The base of each triangle corresponds to the estimated time of dropping HIV-1 RNA levels below 50,000 (4.7 log₁₀) copies/ml for each subject. In all subjects estimation of high viral load duration is outlined by gray shading delineating the time from seroconversion to the last observation before cART. In addition, in three subjects —A-1811, OQ-2990, and RB-6380—yellow shading corresponds to estimation of high viral load duration using the Kaplan-Meier method. Six-month interval HIV testing is delineated at the top, and 12-month interval testing is shown at the bottom.