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INTRODUCTION — Primary HIV-1 infection can present as a mononucleosis type of syndrome with a constellation of otherwise nonspecific symptoms. Without a high index of suspicion, the diagnosis can frequently be missed by well-intentioned physicians.
Establishing the diagnosis of primary HIV infection is clearly important from the public health perspective. Patients are typically highly infectious during acute HIV due to an enormous viral burden in blood and genital secretions. Such patients may be unaware that they are infected and continue to engage in risky sexual activity and needle-sharing.
Mathematical models suggest that a large proportion of all HIV infections may be transmitted by individuals with primary infection. This was illustrated in a retrospective study of 235 monogamous, HIV-discordant couples in Uganda, HIV transmission was confirmed by viral sequence analysis in 68 patients. The highest rates of acquisition were among partners of patients who recently acquired HIV followed by those with end-stage AIDS.
However, the period of greatest risk is in the early stages of acute HIV, which is associated with a very high viral load and no detectable antibody.
The diagnosis and treatment of primary HIV will be reviewed here. The pathogenesis, epidemiology, and clinical manifestations of this infection are discussed separately. (See "Primary HIV-1 infection: Pathogenesis; epidemiology and clinical manifestations").
ESTABLISHING THE DIAGNOSIS — The diagnosis of acute HIV infection is infrequently made in clinical practice. In the case series from Seattle, for example, the diagnosis of HIV infection was considered in only 5 of 19 patients (26 percent) who sought care from their primary care physicians, emergency departments, and walk-in clinics. This finding was especially surprising since these patients were enrolled in a surveillance program for HIV.
There are several reasons why acute HIV infection is so infrequently diagnosed:
The symptoms — especially in mild cases — are nonspecific and resolve spontaneously without treatment.
Clinicians may be uncomfortable raising the question of sexual exposure or intravenous drug-use, especially with patients whom they only see infrequently such as young, previously healthy individuals.
Primary care physicians may not be aware of high-risk behavior even in patients they know well. Such patients often choose to undergo counseling and serial serologic testing at an anonymous clinic rather than to discuss risk behaviors with their primary care provider.
Patients may not perceive themselves to be at risk. We have seen several men who acquired HIV through receptive oral sex and expressed surprise that this was a mode of HIV transmission.
Given the importance of establishing the diagnosis of acute HIV infection both for the individual and for its public health implications, we propose the following approach to the patient who presents with an ill-defined febrile illness, heterophile-negative mononucleosis-like syndrome, and/or aseptic meningitis:
Question all patients about HIV risk behaviors including sexual activity and injection drug use.
Perform a thorough physical examination with particular attention to the signs of primary HIV infection such as rash, mucocutaneous ulcers, and lymphadenopathy.
Perform a baseline HIV antibody test. This serves two important purposes: it establishes whether chronic HIV infection is present, and it initiates a discussion about the implications of HIV testing with the patient since most states require informed consent for HIV antibody testing.
Obtain an HIV viral load test.
The diagnosis of acute HIV infection is established by demonstrating a high viral load or a positive p24 antigen in a patient with typical clinical features and a negative or indeterminate HIV serologic test. Biopsy of a skin lesion usually does not assist in the diagnosis of primary HIV infection due to the nonspecific nature of the histopathologic changes.
Viral load — Patients with acute HIV have a markedly elevated viral load, easily detectable with regular (as opposed to ultrasensitive) viral load tests. In one study, for example, all patients with acute HIV had values >100,000 copies/mL. An additional finding in this study was the occurrence of false-positive viral loads in 8 of 303 patients without HIV infection, for a false-positive rate of 2.6 percent.
Importantly, all of the false-positives had <2000 copies/mL, making them easily distinguishable from the true positives whose values were much higher. Furthermore, all of the false positives occurred with the bDNA rather than RT-PCR version of the test.
As a result, the preferred test is the RT-PCR version with a lower-limit cutoff of 400 copies/mL. A false positive test should be suspected if the viral load is low (<10,000 copies/mL) in the setting of suspected acute HIV infection. A repeat sample should be drawn in this setting; a rising viral load suggests a true positive result.
Nucleic acid amplification testing (NAT) is a sensitive method to detect acute HIV viremia in patients who are antibody negative. However, NAT is an expensive test to utilize as a screening tool for the detection of acute HIV infection in large populations. Interest in the use of pooled specimen testing to decrease the cost of the assay has increased due to the ability of NAT to detect HIV RNA at levels of 75 copies/µL or lower.
The addition of pooled specimen NAT to standard HIV antibody testing was evaluated for the detection of acute HIV in 109,250 persons at risk in North Carolina. Chronic HIV infection was diagnosed in 583 patients by standard ELISA and Western blot assays; of these, 107 infections were recently acquired as identified by detuned ELISA testing. Use of NAT on 108,667 samples with negative or indeterminate results on standard antibody assays detected an additional 25 subjects with viremia. Acute HIV infection was confirmed in 23 patients. (See "Serologic studies" below).
A p24 antigen assay is a less costly but also less sensitive alternative to viral load testing, and in one series was falsely negative in 5 out of 54 patients with acute HIV. (See "Techniques and interpretation of HIV-1 RNA quantitation").
Serologic studies — Primary HIV infection is ultimately confirmed serologically by the appearance of antibodies to HIV. (See "Serologic tests for the diagnosis of HIV infection"). In one study of eight patients with symptomatic primary HIV infection, IgM antibody by immunofluorescence assay (IFA) was detected at a mean of 5±3 days and IgG antibodies at a mean of 11±3 days after the onset of symptoms. However, the standard third generation enzyme linked immunosorbent assays (ELISAs) used in clinical practice and in blood banks in the United States do not detect antibodies to HIV until three to seven weeks after infection.
Very early treatment for primary HIV infection has rarely led to abrogation of HIV antibody responses. In a cohort of 150 patients with symptomatic primary HIV infection that was treated with antiretroviral therapy, three patients did not develop a fully evolved antibody response and/or demonstrated evidence of seroreversion after successful HIV RNA suppression. In another study of 75 acutely infected patients who had positive EIA antibody results at the time of initiation of HAART, five subsequently developed a negative result on at least one second generation EIA test. It has been postulated that maturation of the humoral response was thwarted by rapid HIV RNA suppression early in the course of disease. It is critical that physicians and patients understand that seroreversion does not indicate viral eradication.
"Detuned ELISA"/STARHS — The Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS or "detuned ELISA") is available from some research laboratories and the CDC to establish whether patients with positive HIV antibody tests have recently-acquired HIV. Since such patients have HIV antibody levels that are still rising, a positive test on a currently available (and highly sensitive) HIV ELISA at the same time a less-sensitive ELISA is negative provides strong evidence that the patient has recently seroconverted, and that HIV acquisition has occurred within the previous 170 days. The use of the less-sensitive ELISA has been helpful in defining HIV incidence among groups of patients who already have a positive HIV antibody test.
Use of the detuned ELISA may aid public health interventions by highlighting important demographic information regarding recently infected populations. In one study, based in Australia during a period of rising numbers of HIV diagnoses, the use of the detuned ELISA identified 132 incident infections from 317 specimens identified through surveillance. Of note, it also misclassified 13 specimens in patients who had laboratory markers of advanced disease.
Genotype resistance testing — The transmission of HIV strains resistant to currently available antiretroviral drugs has been demonstrated. These strains are strongly influenced by drug use patterns in the source. (See "Primary HIV-1 infection: Pathogenesis; epidemiology and clinical manifestations"). As a result, we now recommend that all patients with documented primary HIV infection also undergo resistance testing after the diagnosis has been established. While both genotype and phenotype testing is available, our current preference is for genotype testing since the procedure is more standardized, the cost of the test is lower, and the turnaround time is faster (approximately two versus three to four weeks). In the absence of antiretroviral therapy, drug resistance tests appear to be able to detect resistance longer in patients who are initially infected with a drug-resistant strain of HIV (primary drug resistance) than in patients who develop secondary drug resistance. (See "Drug resistance testing in the clinical management of HIV infection").
Prevention counseling — All patients with suspected or confirmed acute HIV infection should be counseled to adopt behaviors that guard against HIV transmission, including consistent and correct condom use and avoidance of sharing injection drug use equipment. There is a particularly high risk of transmission during primary HIV infection, when virus loads are often exceedingly high (100,000 to one million copies/mL compared to an average viral burden without therapy of 30,000 to 50,000 copies/mL in chronic infection).
TREATMENT
Rationale for treatment — After a diagnosis of acute HIV infection is made, patients should ideally be referred to an HIV specialist for consideration of antiretroviral therapy.
Preliminary data suggest that treatment of acute HIV infection may result in preservation of HIV-specific cellular immune function and establishment of a lower viral set point. Additionally, antiretroviral therapy may lead to decreased B cell activation, reduction of apoptosis, and restoration of memory B cell pools. However, not all studies have suggested such a benefit on viral set point. Further potential advantages of early intervention include:
Reduced risk of viral transmission
Decreased severity of the symptoms of the acute infection
Limitation of viral mutation, including the evolution of drug resistance
Long-term control of cellular reservoirs
Potential risks — The theoretic benefits of early treatment must be balanced against the possible risks, including:
Higher risk of long-term antiretroviral drug toxicities due to a considerable increase in the duration of antiretroviral exposure
Evolution of drug resistance if therapy fails to completely suppress viral replication
The latter point emphasizes the critical need for patient commitment to strict adherence if treatment is initiated during acute infection when the rate of viral replication is particularly rapid. As noted above, acquisition of a drug-resistant strain of virus is also a possibility, and a resistance test should be done after the diagnosis of acute HIV is confirmed.
Clinical data — Since acute HIV infection is seldom recognized in clinical practice, data about outcomes of early antiretroviral therapy are limited. A prospective longitudinal analysis of clinical markers in 102 patients with primary HIV infection was performed to assess the risks and benefits of early treatment intervention. Patients were divided into two groups on the basis of the phase of HIV infection at the time of initiation of treatment. Preseroconversion was defined by the presence of HIV-1 RNA and negative results of HIV-1 antibody testing. Postseroconversion status was defined by positive results of HIV-1 antibody testing with evidence of seroconversion occurring with the previous 12 months. Fourteen patients who subsequently underwent a structured treatment interruption were excluded from analysis. The study was significant for the following observations:
41 patients (40 percent) were treated during the preseroconversion phase and 55 (54 percent) had already experienced seroconversion.
The mean nadir CD4 count of 422 cells/µL increased to a mean of 702 cells/µL at 12 months and there was a continued incremental increase in CD4 counts over 60 months for subjects who remained on therapy. Ninety-seven percent of patients also achieved virologic suppression which was durable in the vast majority at 18 months of follow-up.
There was no significant difference in absolute CD4 counts or time to virologic suppression for the pre- and postserconversion groups.
Time to viral suppression was similar regardless of treatment regimen. Fifty-two percent of patients discontinued at least one drug from their initial antiretroviral regimen secondary to side effects.
This nonrandomized study is not designed to answer the question as to whether early therapy should be the standard of care for primary HIV infection; however it does provide some data regarding clinical expectations of the risks and benefits of treatment.
Patient management — Given that antiretroviral therapy for acute infection remains controversial, enrollment in a research study is encouraged to provide more information for clinicians about the outcome of early intervention. Listings of available trials can be found at
www.clinicaltrials.gov. If referral to an HIV specialist or enrollment in a protocol is not feasible, treatment should be initiated following the latest consensus guidelines on antiretroviral therapy. At this juncture, there are not sufficient data to make recommendations about specific drug combinations for acute HIV infection.
US Department of Health and Human Services (DHHS) guidelines suggest selection of the same potent regimens recommended for chronic HIV infection. Regimens recommended by DHHS [27] and by the International AIDS Society-USA Panel are discussed separately. (See "Initial antiretroviral therapy for HIV infection", section on Regimens). It is particularly important that all medications in the antiretroviral regimen are started simultaneously to minimize the development of drug resistance during this period of rapid viral replication.
Duration of treatment — The appropriate duration of therapy for acute HIV infection is unknown, but is felt by most experts to be at least two to three years and perhaps lifelong.
However, there have been case reports of patients treated during acute infection who were able to come off of therapy and control the viral load at a relatively low level. It was proposed that immunologic control may be related to virus-specific CD4 responses, which are lacking in most patients with chronic infection, even when an undetectable viral load and a relatively normal quantitative CD4 cell count are achieved. One of the goals of early treatment is to stimulate these critical HIV-specific CD4 responses.
An early report described eight patients treated with combination antiretroviral therapy within 72 hours of the diagnosis, five of whom achieved virologic control after either a first or second treatment interruption for a median of 6.5 months off of therapy. Treatment of acute HIV in these patients led to a vigorous, HIV-specific CD4 response similar to that seen in long-term nonprogressors; the purpose of the treatment interruptions was to boost HIV immunity through reexposure to HIV antigens.
However, formal testing of this proof-of-concept in larger trials has been thwarted by the difficulty in identifying patients with acute HIV infection; furthermore, the results of one small multicenter study (PRIMSTOP) was not as encouraging as the above case report. This multicenter, prospective trial formally evaluated structured treatment interruptions in 29 patients with early symptomatic primary HIV infection. A 34-week treatment phase was followed by three consecutive periods of two, four, and eight weeks off HAART, each separated by 12 weeks on HAART. Treatment was permanently stopped at week 84 and patients were followed up for 24 weeks for assessment of virologic success. Six months after discontinuation of therapy, only one patient had a non-detectable plasma viral load; six patients had a viral load <1000 copies/µL, and three patients developed a major mutation to protease inhibitors (L90M). These data suggest that the vast majority of patients who initiate HIV therapy in the setting of acute infection fail to suppress viremia.
At this time, patients with primary HIV should be enrolled in clinical trials since the benefits of early treatment are still unclear. The optimal schedule of treatment interruption, the risk of selecting for resistant virus, and the risk of recurrent symptoms of acute HIV (see below) all still remain to be defined.
COMPLICATIONS OF TRANSIENT IMMUNOSUPPRESSION — Although usually associated with later stage HIV disease, opportunistic infections can occur during the transient CD4 lymphopenia of primary HIV. Oral and esophageal candidiasis is the opportunistic infection most often seen in these patients. The factors responsible for the frequency of esophageal candidiasis during the immunosuppression of acute HIV infection are not well understood. Two possibilities are that esophageal ulceration provides a local environment which promotes the growth of Candida species, and that the administration of antibacterial antibiotics to empirically treat primary HIV may alter normal oropharyngeal flora
Case reports of other opportunistic infections seen during acute HIV infection include:
One case of CMV proctitis in a young man with rectal pain and bleeding in association with more typical features of the acute retroviral syndrome.
Colonoscopy showed diffuse edema, erythema, and friability of the rectal mucosa; biopsy revealed characteristic inclusion bodies in the vascular endothelium and lamina propria. The proctitis symptoms spontaneously improved within several weeks; repeat rectal biopsy confirmed resolution of CMV.
Three patients with Pneumocystis carinii pneumonia 8 to 14 days after initial presentation with primary HIV infection [37]; CD4 counts were very low (63 to 91/µL) in these patients.
One case of severe and prolonged cryptosporidiosis complicating acute HIV infection.
Several patients have acquired thrush.
RECURRENT SYMPTOMATIC ACUTE HIV — Several case reports have described a clinical syndrome resembling primary HIV in patients with chronic HIV infection who discontinued effective antiretroviral therapy. Symptoms including fever, lymphadenopathy, and rash developed in four patients ten days to four weeks after discontinuing all antiretroviral drugs. Viral loads which had been <50 copies/mL in all of the patients rose dramatically to as high as 1,000,000 copies/mL and CD4 counts dropped appreciably. Resumption of therapy produced resolution of symptoms, decrease in viral load, and increase in CD4 counts. Cases of recrudescent symptomatic acute HIV have also been reported in patients treated during acute infection who have stopped treatment.
Sincerely,
Dr. AKA_Monet
GC Chief Healthcare Officer
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