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ACUTE HIV INFECTION: THE ENGINE OF HIV TRANSMISSION and A PRIME TARGET FOR ANTIRETROVIRAL THERAPY; odds of transmission per sex act
Reported by Christopher D. Pilcher, MD of the University of North Carolina at Chapel Hill Center for AIDS Research
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Acute HIV infection is a term that relates not to the severity of illness, but to the recent nature of infection. Also called Primary HIV infection or PHI, this period of a few months following initial infection is characterized by skyrocketing virus loads in both blood and genital secretions. While this transient state of high viremia subsides after a month or two, it has been long suspected that acutely infected men and women would be highly infectious. Still, the period of high viremia is very brief (one-two months) and its importance as an engine of transmission in populations has been the subject of some controversy over the years.
Wawer and colleagues from Hopkins (Oral Abstract 40) presented new data at the Retrovirus conference that may go a long way toward settling this critical issue. The Rakai study was a very large, observational cohort study enrolling Ugandan couples in which only one partner was HIV seropositive, and then following the uninfected partner over time for evidence of seroconversion. Couples from villages participating in the study were screened approximately once every 10 months; in some cases, couples both initially screened as HIV negative but one or the other partner proved positive at the next screening session. In all, 23 of 240 total monogamous HIV-discordant couples were thus identified where the positive individual was newly infected. 166 couples contained an HIV positive individual with pre-existing, early-stage HIV infection and in an additional 51 cases, the positive partner had late-stage disease (dying during the course of the study). By taking detailed sexual histories and in effect counting the sex acts within these partnerships, Rakai investigators were able to calculate the odds of transmission per penile-vaginal sex act for each of these disease stages. The results of this comparison were stunning: the odds of transmission averaged over the first five months of infection were estimated to be 8-10 fold higher per sex act than after 5 months of infection. Transmission odds for patients with late-stage infection were somewhat higher than during middle-stage disease but never reached the magnitude associated with acute infection. Most compelling, Wawer and colleagues estimated that nearly half (43%) of newly infected patients transmitted to their partners after only five months of infection and that rates plummeted after that. Gender and HIV-related symptoms were not independently associated with transmission in the study.
These data are profoundly important in that they appear to explain the apparent paradox of low heterosexual transmission rates in chronic HIV infection and a burgeoning pandemic dominated by heterosexual spread. IfÑas this study strongly suggestsÑthe lionÕs share of heterosexual transmission happens very early in infection, then recognizing patients early (rather than at the time of AIDS) could become a critical opportunity for preventing HIV transmission in populations.
Is large-scale diagnosis of acute HIV possible?
A number of presentations considered controversies in the diagnosis and management of patients with acute HIV. A study from the Malawi UNC Project presented on Thursday (Session 154) showed that as many as 5% of HIV antibody-negative men screened for HIV in a Malawian STD clinic actually had acute HIV infection as demonstrated by having high levels of HIV RNA in blood. While shocking, these numbers give reason for optimism that potentially large numbers of African patients could be identified, counseled and/or treated at the time of their peak infectiousness.
To treat or not to treat?
For acutely infected patients, there are two main benefits that go with being identified: first, the opportunity to avoid unwittingly infecting intimate partners; second, and equally compelling, is that the period of acute infection could be the only time that a SHORT course of HAART can improve overall prognosis. Three years ago, Eric RosenbergÕs preliminary studies of a highly selected group of patients in Boston suggested that early, aggressive HAART followed by structured treatment interruption might enhance patientsÕ immune control of the virus and lower viral loads off of therapy. However, it is possible that these early results are not generalizable to all patients or to all treatment regimens. The stakes for acutely infected patients are quite high, since generally speaking they are years from having to otherwise initiate therapy according to current guidelines and hence have much to lose by prematurely starting HAART.
In a poster on Thursday (Abstract 519), Hecht and colleagues presented followup data on an observational cohort of 231 patients identified at the time of acute infection across the US: 62 patients had been treated with a brief course of HAART (and then stopped) and 169 patients were untreated. Compared 24 weeks after treatment interruption, the treated-then-interrupted patients indeed had lower viral loads and higher CD4 counts than the untreated group; for patients diagnosed within 6 weeks of infection, viral loads were over a log lower (3.1 vs 4.3 log copies/ml HIV RNA) 24 weeks after final interruption. The difference was less striking (3.5 vs 4.2 log) for patients identified between 6 and 12 weeks from infection. While these differences barely scraped statistical significance, and patients were not randomized to treatment or no treatment (and hence differences between the groups could be explained by other factors), these are still the first "real-world" data to support the potential value of early, aggressive but temporary HAART as an effective strategy for managing acutely infected patients.
HU and IL-2: friend or foe in acute HIV?
A number of strategies including 4 or 5 drug HAART, IL-2 and HU (hydroxyurea) have been proposed for managing patients with acute infection; to date, none has been shown to be superior. Trials employing a number of regimens as temporary HAART (used with a variety of strategies and schedules for treatment interruption) were presented as posters at the conference. The PRIMSTOP trial (Abstract 512) used ddI/d4T/HU/nelfinavir for 9 months before initiating a series of up to 3 STIs: about half of patients in this ongoing trial appear to be maintaining viral loads <10,000 copies per ml during STIs, but there also appeared to be little improvement in control of viremia between first and third STI for most patients. A non-randomized cross-cohort comparative study presented by Lafeuillade and colleagues, also from France, (Abstract 513) compared acutely infected patients treated with ddI/d4T/HU/SQV and IL-2 to a group treated with 3 (unspecified) NRTIs. They found that despite apparent virologic control to <50 copies in blood in both groups on therapy, the ddI/d4T/HU/SQV/IL-2 treated group tended to have worse HIV Ðspecific immune responses than the 3-NRTI group after 24 months on therapy, and also tended to have larger residual HIV reservoirs as measured by circulating proviral DNA. After 1-3 STIs, only 2/15 patients in the ddI/d4T/HU/IL-2 group controlled viremia at levels <50 copies, as compared to a remarkable 12/15 in the 3-NRTI group who maintained <50 copies/ml off therapy. The striking differences in responses to the two regimens (favoring the 3-NRTI regimen) appeared to be best explained by the differences in proviral DNA and HIV-specific immune responses seen in the groups, when examined in multivariate analysis. While the numbers in both this study and the PRIMSTOP trial are very small, it is noteworthy that differences in treatment regimens may result in very different immunologic responses to HAART initiated during acute infection. It is premature to declare that HU or IL-2 (or SQV for that matter) are inappropriate for early HAART therapy; however, two things are clear: 1) all "potent" regimens are not necessarily created equal in acute infection, and 2) the theoretical arguments for using immuno-modulatory agents such as IL-2 and HU as part of early HAART in this setting need to be carefully examined in rigorously designed clinical studies.
While the importance of identifying acute infections has been dramatically emphasized by the Rakai data, the best ways to identify acutely infected patients remain the subject of intense study and present tremendous opportunities for public health. The opportunities for improving the health of newly infected individuals are tantalizing, but results of early studies are maddeningly inconsistent. If more acute infections can be identified by primary care physicians, infectious disease doctors and public health systems, the randomized clinical trials necessary to provide the answers for effective therapy and prevention may come all that much quicker.
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