To the Editor:
In a very interesting report, Vicenzi et al1 examine the virologic state of seven individuals with long-term nonprogressors characteristics (LTNPs) selected from a well-characterized cohort of human immunodeficiency virus (HIV) infected hemophiliacs. One of the most important observations was that LTNPs showed significantly lower viral load and replication, determined by quantitative polymerase chain reaction (PCR), when compared with progressors. According to their report a threshold of approximately 10,000 copies of HIV RNA/mL plasma characterizes the LTNPs population. In a previous study by Cao et al,2 the values of HIV RNA ranged from 839 to 11,549 copies of HIV RNA/mL of plasma in LTNPs in which the route of infection was intravenous drug use or unprotected homosexual sex. The method of quantitation RNA in plasma used by Cao et al2 was a modification of the branched-DNA signal-amplification assay. In another report, Pantaleo et al3 studied 15 nonhemophiliacs with long-term nonprogressive HIV infection. The method of quantitation viral load was quantitative PCR, as in the study of Vicenzi et al,1 but they found higher levels of HIV RNA (the threshold for this author was 70,000 copies/mL) in LTNPs patients. In their report, Vicenzi et al1 argued that these differences reflect distinct populations of infected individuals.
In our center we have studied 82 hemophiliacs infected with HIV, 6 of whom fit the definition of LTNPs according to the criteria of Vicenzi et al1: infection lasting for at least 10 years, absence of HIV-associated symptoms, CD4+ T-cell counts of at least 500 cells/μL blood, and no antiretroviral therapy. The levels of viral load are shown in Table 1. Moreover, we have studied the levels of viral load in six hemophiliac progressors age- and sex-matched and infected in the same period. The technique for estimating HIV RNA in plasma in our study is similar to those of Vicenzi et al1 and Pantaleo et al.3 Our results show higher levels of viral load in LTNPs than in progressor. The threshold of approximately 10,000 copies of RNA HIV/mL plasma that characterizes the population of LTNPs of Vicenzi et al1 is higher in 2 of our patients (patients no. 2 and 6), but the mean of LTNPs are 10,016 copies of RNA HIV/mL plasma versus 271,333 in the progressors population.
In conclusion, the viral load in LTNPs hemophiliacs is substantially lower than in hemophiliacs progressors but can be slightly higher than the threshold of 10,000 copies of RNA/mL plasma found by Vicenzi et al.1 We believe that these differences can be due to the small number of LTNPs in ours studies.
Response
In a study investigating plasma viremia in human immunodeficiency virus (HIV)-infected hemophiliacs with characteristics of long-term nonprogressors (LTNPs), Jimenez-Yuste et al describe individuals with a virological status similar to that reported by us,1-1 although with two notable exceptions. In our original studies, we have indicated an arbitrary cut-off value of about 10,000 copies of HIV RNA/mL of plasma below which all LTNPs hemophiliacs fit, whereas almost all control infected hemophiliacs with progressive disease had viral load levels above this value.1-1 Of interest, the control hemophilic progressors of Jimenez-Yuste et al show a mean value of plasma viremia very similar to what reported by us (271,333 v 284,521 HIV RNA copies/mL, respectively), despite the broad range shown by individual patients. In contrast, a higher level of viremia appears to characterize their LTNP hemophiliacs compared with ours (10,016 v 2,465 HIV RNA copies/mL of plasma, respectively). On this basis, the authors question the validity of the “10,000 copies threshold” concept, and, more importantly, point out that viremia levels in two of their patients largely exceed this value. Plasma viremia levels from an 18-month follow-up of our cohort of hemophilic LTNPs are shown in Table 1-1. These results suggest two important considerations. First, the possibility that different levels of viremia are the consequence of different methodologies implied in the studies appears of not particular relevance, particularly at low levels of viremia. Second, it is worthy of note that although 5 of 7 of our LTNPs remain essentially stable in terms of viremia (likely reflecting a well-controlled HIV infection), patient no. 3 has “crossed” the 10,000 copies threshold, and patient no. 2 is very close to it, making our small cohort today more similar to that reported here by Jimenez-Yuste et al. However, it should be noted that our patient no. 3 was already characterized by the highest viremia level at the time of the original study (Table 1-1). We agree with Jimenez-Yuste et al that larger studies on LTNP are warranted, but we also believe that these highly selected individuals, reaching in some cases 13 or more years since infection, and in good healthy conditions except for beiing hemophiliacs, are important biological exceptions in the natural history of HIV disease. Arbitrary thresholds, such as that of 10,000 copies, should simply be viewed as tools to study larger populations of individuals, whereas, at the same time, intra- and inter-assay variabilities should not be forgotten. Whether evolution of HIV disease, or, hopefully, the lack of it, can reliably be monitored by plasma viremia even in LTNPs remains a working hypothesis that only time will confirm or invalidate.
