Treating Primary Infection
Does Early Intervention Alter the Course of HIV Disease?
The prevalence of HIV infection continues to increase.(1) As of the end of 1992, the last year for which complete statistics are published, between 650,000 and 900,000 individuals -- 0.3% of the total population of the United States -- were infected with HIV, and another 520,000 had died of AIDS.(2) Although the yearly incidence of new infections has not increased at the same rate that it did during the early years of the epidemic, the total number of people who are infected each year continues to increase. The prevalence of HIV infection among young men who have sex with men is as high as 11%, and the annual seroconversion rates among injection-drug users and crack cocaine users remains frighteningly high, with an additional 4% to 5% of these groups becoming infected every year.(3, 4)
Most -- but not all -- of these newly-infected individuals will manifest some symptoms of primary HIV infection at the time infection occurs. Alert clinicians, other healthcare providers, and community outreach workers who learn to recognize these symptoms can assist in the early identification and prompt treatment of primary infection. Early intervention can lead to a substantial reduction in viral replication in recently infected individuals, and aggressive antiretroviral therapy may be able to forestall the development of HIV-related infections and prolong life.
Intervention during primary HIV infection represents an important new front in efforts to combat the HIV epidemic. Recent evidence suggests that events in the first weeks after exposure are critical in the pathogenesis of HIV disease, and these events influence the course of the disease for years afterward.(5-11) It is hoped that treating people with primary HIV infection will reduce the virologic set-point for newly-infected persons at the same time that early therapy advances our understanding of the pathogenesis of HIV disease and provides us with an important new treatment tool.
Considerable effort is now being expended at a number of HIV treatment centers to identify, recruit, and treat persons with primary infection. Not all people with suspected primary HIV infection will prove to be newly infected, but by identifying and evaluating high-risk individuals with symptoms of recent infection we increase the likelihood that we will pick up a significant number of new infections.
Moreover, these efforts, even when they fail in their primary purpose, do serve another all-important function: They expand our ability to deliver risk-reduction interventions to those who need them most, and this intervention may heighten awareness -- and thereby reduce the rate of infection among those at highest risk for exposure to HIV.
Signs and symptoms of primary HIV infection
During initial infection, there is period of intense, unchecked viral replication, reflected by a heavy burden of plasma viremia, p24 antigenemia, and high titers of HIV in peripheral blood mononuclear cells (PBMC).(12-20) This high level of viremia declines with the development of cell-mediated immune responses to HIV. The exact nature of the immunologic events that reduce viral titers are unknown, but they include development of cytotoxic T cell responses and, perhaps, cytokine-derived cellular responses.
Initial HIV infection is often accompanied by signs and symptoms of acute retroviral infection (Table 1). These symptoms can present within days to months of infection. Approximately 80% of newly-infected individuals report a history of viral-like illness. The signs and symptoms of initial HIV infection include fever, headache, myalgia, pharyngitis, lymphadenopathy, maculopapular erythematous rash, aphthous ulcers, retro-orbital pain, shortness of breath, diarrhea, fatigue, lethargy, and malaise.(5, 21-23) In a small number of cases oral candidiasis and ulceration of the esophagus and/or the anus are among the presenting symptoms. Laboratory studies performed during the period of primary HIV infection often reveal lymphopenia and thrombocytopenia. Atypical lymphocytes have also been noted in newly-infected individuals.
Another recent study has shown that the concentration of plasma viral RNA at the end of acute HIV infection predicts the long-term clinical course of disease:(24) a high set-point is associated with rapid progression. By contrast, several studies of so-called long-term non-progressors indicate that low viral burden and vigorous cellular responses are associated with prolonged asymptomatic HIV infection.(10, 11) This suggests a possible benefit to early intervention: effective antiviral treatment during primary infection might lower the set-point of subsequent viral replication and lead to a prolonged period of asymptomatic disease.(24, 25) The link between high viral load and increased risk of disease transmission was also demonstrated in two recent studies involving maternal-perinatal transmission.(26, 27)
Rationale for treatment of primary HIV infection
Support for the concept of treatment during primary HIV infection comes from recent observations which show that HIV may be more vulnerable to antiretroviral agents during primary infection. Newly-infected persons tend to have a relatively homogenous swarm of viruses, whereas persons with long-term infection have a diverse swarm of viruses.(28-30) Where one finds homogeneity of viral swarms during initial infection, one finds low levels of variants that are already resistant to antiviral agents -- and it therefore follows that treatment should be more efficacious during this phase of infection.
Two studies of zidovudine monotherapy following exposure to HIV suggest the utility of treating patients early after exposure (see "Reducing the Risk of Occupational Exposure to HIV," Vol. 1, No. 4, pages 69-73). A retrospective case-control study, using data reported to national surveillance systems in the United States, France and the United Kingdom, investigated post-exposure treatment among healthcare workers.(31) Exposures were limited to those that occurred after 1988 in the United States, after 1989 in the United Kingdom, and after 1990 in France. Demographic data were collected regarding the HIV-exposed healthcare workers, the use of post-exposure antiretroviral agents, and the source patients.
In all, this study considered 31 cases of healthcare workers who became infected and compared information on these individuals with that on 679 matched controls in the healthcare profession who had reported exposure to HIV. Factors that were associated with HIV transmission to health care workers included a deep injury, a device visibly contaminated with the source patient's blood, procedures involving a needle placed directly in a vein or artery, and terminal illness in the source patients. This study found that healthcare workers who did not take ZDV after exposure to HIV were significantly more likely to develop HIV infection than controls who had taken ZDV (adjusted odds ratio = 0.2, p < 0.01).
ACTG 076 -- a randomized placebo controlled study that evaluated the efficacy of ZDV, taken during pregnancy and immediately post-partum, in preventing vertical transmission of HIV -- also demonstrated a dramatic reduction in infection in infants born to women treated with ZDV compared to those treated with placebo.(26) This may be due to the protection that ZDV offers against seroconversion, or due to reduction in maternal viral load, or to both mechanisms (see "AZT Diminishes Transmission of HIV-1 from Mothers to Their Infants," Vol. 1, No. 2, pages 31-35).
Although these two studies do not simulate the treatment paradigm of primary HIV infection, they do suggest that there are benefits to early intervention. Both of these studies were, in essence, prophylaxis trials -- where ZDV was given to reduce the likelihood that actual or suspected exposure to HIV would result in infection. In cases of primary HIV infection, by contrast, infection has already occurred, and the aim of antiretroviral therapy is to reduce viral burden to undetectably low levels. Nonetheless, the C.D.C.'s retrospective case-control study and ACTG 076 are indicators of the powerful effects of early treatment -- before overt symptoms of HIV infection can be detected. These two studies indicate that early identification and treatment can reduce rates of HIV infection, and they suggest that early treatment may also reduce the consequences of infection.
Treatment of primary HIV infection has been tested in a recently concluded randomized, double-blind, controlled clinical trial.(32) Patients with symptoms consistent with acute retroviral syndrome or with known recent exposure to HIV -- all with laboratory evidence of recent infection -- were randomized to either ZDV, 250 mg twice daily, or placebo for six months.(25) (The laboratory evidence for recent infection consisted of the presence of p24 antigenemia with a negative or low positive HIV-1 antibody test.) After six months, CD4 counts had increased a mean of 173 cells/mm3 in the ZDV group, compared with an increase of 6 cells/mm3 in the placebo group.
This difference is more dramatic than anything seen in any studies of ZDV at later stages of HIV disease. During a mean follow-up period of 15 months, minor opportunistic infections such as oral candidiasis or herpes zoster developed in 7 of the placebo patients but only one of the ZDV-treated patients (p = 0.009). Thus, this study provides important clinical trial evidence for the concept of treatment of primary HIV infection.
Three recent investigations demonstrate that certain combinations of antiretroviral agents reduce plasma concentrations of HIV-1 to undetectably low levels. These drug combinations also reduce the immunologic response to HIV (as evidenced by the loss of antibodies to HIV-1), with therapy indicating the elimination of HIV-1 antigens and raising the possibility of viral eradication.(33-35) The first of these studies combined ZDV with an experimental non-nucleoside RT inhibitor, L-697,661. Only four patients were treated, but two of these patients had no detectable virus (< 200 copies of HIV RNA/mL) during treatment. After six months of therapy, treatment was discontinued, and HIV-1 RNA promptly returned to pre-treatment values. Levels of proviral DNA declined with treatment but were always detectable.
A second study, conducted in New York, enrolled 12 people who were identified as HIV-positive within 90 days of infection. These patients were treated with the triple-drug combination of ZDV, 3TC, and ritonavir. Nine patients were compliant with treatment and were available for follow-up. Within four weeks of treatment these nine patients had no detectable virus in their peripheral blood (assay limit: above 500 copies/mL).
The third study examined the effects of combining ZDV and ddI in patients with recent HIV infection, and this drug combination also exhibited potent antiretroviral effects -- including suppression of HIV replication in the lymph nodes of one of the study subjects. These three studies confirm the potency of antiretroviral agents when they are used in combination to treat people with primary HIV infection.
Early identification of recent HIV infection
The symptoms of acute HIV infection are non-specific, and many persons with suspected primary HIV infection will prove to have routine viral illnesses rather than HIV. Clinicians should expect that the majority of the individuals who are evaluated for primary HIV infection will not turn out to be infected with HIV. Nevertheless, this screening process represents an important opportunity to engage these high-risk individuals in discussions about HIV risk-reduction. Therefore, a critical aspect of all efforts to recruit people for treatment of primary HIV infection is the establishment of mechanisms to reduce the risk of those high-risk individuals who are found to be seronegative.
This risk-reduction effort depends for its success upon establishing liaisons between clinicians, behavioral scientists, and those involved in community-based prevention programs (Table 2). It also requires extensive follow-up. Effective risk-reduction programs also rely upon the active participation of members of the targeted groups, who alone can provide reassurance that the prevention is sensitive and appropriate to persons in the target population.
Follow-up is a crucial aspect of all risk-reduction programs, since at initial presentation and testing not all people infected by the virus will have laboratory evidence of infection. Therefore, follow-up at four weeks and perhaps again at six months is needed to confirm or deny HIV infection with standard approved laboratory tests. The optimal timing of viral-load measurements to confirm HIV infection are a focus of ongoing research and clinical investigation.
The UCSF Options Project approach to primary HIV infection
Members of the UCSF AIDS Program and the Center for AIDS Prevention Studies at UCSF have implemented a system, dubbed the Options Project, that will identify and treat people with primary HIV infection. The Options Project's success is based on two concepts:
The studies of primary HIV treatment cited above were based on ZDV monotherapy, which is now considered relatively weak antiretroviral treatment. The Options Project, by contrast, offers participants current state-of-the-art antiretroviral treatments, including triple- and quadruple-drug regimens (Table 3). Activity data will be based on virologic response, as measured by quantitative branch DNA (bDNA) assays in serum and lymph tissue, and CD4 T-lymphocyte counts. Data from this study will provide valuable information regarding virologic and immunologic responses to treatment as well as therapy-associated adverse reactions.
New evidence suggests that events which occur during primary HIV infection have a crucial impact on the subsequent course of disease -- and aggressive antiretroviral treatment during this stage of infection represents a unique opportunity to improve long-term outcomes. The Options Project study will use a multidisciplinary team to implement innovative methods of recruiting persons with primary HIV infection, and it will integrate recruitment and treatment of HIV-infected people with prevention efforts aimed at high-risk individuals who are not infected. This innovative program will also test the ability of several potent antiviral combinations to reduce long-term viral replication in persons with primary HIV infection.
Intervention during primary HIV infection is an important new front in efforts to combat the HIV epidemic. The Options Project will contribute important advances in developing recruitment strategies, treatment regimes, and integrated HIV prevention efforts for primary HIV infection.
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James O. Kahn, M.D., and Frederick Hecht, M.D., are with the UCSF AIDS Program, San Francisco General Hospital, San Francisco, CA.
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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.