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Treatment of Primary Human Immunodeficiency Virus Type 1 Infection with Potent Antiretroviral Therapy Reduces Frequency of Rapid Progression to AIDS

  1. M. Michelle Berrey1,a,
  2. Timothy Schacker5,a,
  3. Ann C. Collier1,
  4. Theresa Shea1,4,
  5. Scott J. Brodie2,
  6. Douglas Mayers6,
  7. Robert Coombs1,2,
  8. John Krieger3,
  9. Tae-Wook Chun7,
  10. Anthony Fauci7,
  11. Steven G. Self5 and
  12. Lawrence Corey1,2,4
  1. Departments of
  2. 1Medicine,
  3. 2Laboratory Medicine, and
  4. 3Urology, University of Washington, and
  5. 4Program in Infectious Diseases Clinical Research Division and
  6. 5Biostatistics, Fred Hutchinson Cancer Research Center, Seattle;
  7. 6Henry Ford Hospital, Detroit, Michigan;
  8. 7Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
  1. Reprints or correspondence: Dr. Lawrence Corey, Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, 1100 Fairview Ave. N, Rm. D3-100, PO Box 19024, Seattle, WA 98109 (lcorey{at}u.washington.edu)
 
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Abstract

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9–12 months, HIV-1 remained detectable in latently infected CD4+ T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS

After primary infection, human immunodeficiency virus type 1 (HIV-1) rapidly and widely disseminates; plasma HIV-1 RNA levels may be >6 log copies/mL, and HIV-1–positive cells are detectable throughout anatomic and cellular reservoirs, including lymph nodes and resting CD4+ T cells [1 –6]. Immunologic perturbations include a gradual decrease in HIV–1–specific memory cytotoxic T cell response and alterations in T cell repertoire [7 –10]. These observations have provided a theoretical rationale for the initiation of aggressive antiretroviral therapy during primary HIV-1 infection [11 –16]. It remains unclear whether immediate antiretroviral therapy yields measurable clinical benefit

Clinical studies of reverse-transcriptase (RT) inhibitors initiated during primary HIV-1 infection have shown modest effects on HIV-1 plasma load, increases in CD4+ T cell counts, and less frequent oral candidiasis and varicella zoster reactivations [17 –21]. Highly active antiretroviral therapy (HAART) regimens containing protease inhibitors (PIs) have demonstrated profound suppression of plasma HIV-1 RNA levels and associated increases in CD4+ T cell counts [22, 23]. During chronic HIV-1 infection, combination antiretroviral regimens containing a PI have demonstrated clinical benefit in morbidity and mortality [24 –27]. However, applicability of these data to justify the initiation of antiretroviral therapy during primary HIV-1 infection may be confounded by the high level of HIV-1 replication during this time and the related potential for mutations that confer resistance, the potential lack of clinical benefits in persons not yet manifesting AIDS-associated conditions, and the potential long-term toxicity of combination regimens in persons who will theoretically require lifelong treatment. Despite these concerns, there is widespread advocacy for early intervention [11 –15]

Since the establishment of a clinic devoted to acute HIV-1 infection in 1993, uniform enrollment and follow-up procedures for patients with clinical, serologic, and virologic evidence of acute HIV-1 infection have been followed [7, 28 –31]. The present study compares the clinical and virologic outcome of 67 consecutively enrolled patients who did or did not initiate combination antiretroviral treatment within the first 90 days of HIV-1 infection

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Patients and Methods

Study populationTo evaluate the effects of immediate therapy on clinical outcome, we compared the virologic and clinical course of patients with primary HIV-1 infection who were seen within 90 days of onset of acute retroviral illness or within 90 days of a documented acute asymptomatic HIV-1 seroconversion [28 –31]. The control cohort for this study consisted of 47 patients who were seen within 90 days of infection (onset of symptoms of seroconversion, evolving Western blot, or recent ELISA seroconversion) from September 1993 through June 1996. During these years, therapy was not initiated at enrollment; antiretrovirals were initiated only later in the course of infection, according to treatment guidelines based on CD4+ T cell count, clinical course, and, subsequently, plasma HIV-1 RNA levels (see below) [27, 32]. This cohort of patients is referred to as the delayed-treatment cohort

In 1996, when the benefit of combination therapy with indinavir was demonstrated, we initiated an investigation to evaluate the effects of indinavir (800 mg 3 times daily), zidovudine (200 mg 3 times daily and then 300 mg twice daily as this became available), and lamivudine (150 mg twice daily) on the clinical and virologic course of early HIV-1 infection [23 –26]. The purpose of limiting therapy to those seen within the initial 90 days after infection was to evaluate whether eradication of HIV-1 from lymphoid reservoirs was possible with the initiation of potent antiretrovirals early in the course of disease. From July 1996 through June 1998, 23 patients with acute HIV-1 infection were enrolled. Of these 23 patients, 20 accepted therapy and were included in the study, 2 declined therapy, and 1 was excluded from indinavir therapy because of a history of renal calculi

An intent-to-treat analysis was used, in which all delayed-treatment patients were considered to be untreated for the entire 78-week period, even if antiretroviral therapy was used later. Of the 47 delayed-treatment patients seen from 1993 through 1996, 40 received no antiretroviral therapy during the 78-week follow-up, 7 initiated stavudine or zidovudine monotherapy within 6 months after enrollment (mean, 105 days; range 41–154 days), 2 initiated therapy with 2 nucleoside RT inhibitors 26 and 52 weeks after enrollment, respectively, and 2 began combination regimens containing PIs 52 weeks after HIV-1 infection. Thus, our analysis largely compares a HAART with an untreated group; however, since 11 patients in the delayed-treatment group initiated some antiretroviral therapy during follow-up, our analysis, especially after week 52, is conservative and somewhat weighted against demonstrating the benefit of early therapy

Patients underwent a standardized medical history and physical examination at enrollment. Follow-up included biweekly visits for 2 months, monthly visits during the remainder of the first year, and quarterly visits thereafter. Patients receiving a combination of antiretrovirals had additional visits at weeks 1 and 3. Standardized case-report forms were used at each study visit, and samples were obtained for virologic and immunologic assays at standardized time points, as described elsewhere [28 –31]. Toxicities to medications were graded according to the Division of AIDS, National Institute of Allergy and Infectious Diseases, toxicity scale [33]. Standardized drug modifications were stipulated in the treatment protocols. Substitution of stavudine was permitted for zidovudine intolerance. Dose adjustments were not permitted for zidovudine, lamivudine, or indinavir. Centers for Disease Control and Prevention (CDC)–defined opportunistic infections and other mucocutaneous and respiratory conditions were confirmed by medical evaluation at a study visit or by patients’ primary care providers [34]. Between 9 and 12 months, all patients were asked to undergo excisional lymph node biopsy; 7 initially untreated and 5 treated patients consented

Laboratory methodsThe diagnosis of acute HIV-1 was made by previously defined criteria. In brief, patients had a documented test result negative for HIV-1 or compatible acute retroviral syndrome and confirmed seroconversion to HIV-1 [22, 28 –31]. HIV-1 isolation, quantitative microculture, syncytia formation (MT-2 assay), and plasma HIV-1 RNA assays were performed, as described elsewhere [28 –31]. Plasma HIV-1 RNA was assayed by use of a branched-chain DNA assay (Chiron Diagnostics), which has a lower limit of detection of 500 HIV-1 RNA copies/mL [35]. In addition, all samples with <1000 HIV-1 RNA copies/mL subsequently were assayed in the Roche Diagnostic Systems ultrasensitive RT–polymerase chain reaction (RT-PCR) assay, which has a lower limit of detection of 50 HIV-1 RNA copies/mL of plasma [36]. Total HIV-1 DNA was determined in CD4+ T cells by use of a quantitative-competitive PCR EIA method [37]. This assay measures both integrated and unintegrated viral DNA, as well as linear and circular forms of viral DNA, and relies on the coamplification of an internal quantitation standard. Phenotypic and genotypic analyses for resistance mutations were conducted at the Henry Ford Health Center (Detroit), using methods described elsewhere [38 –40]

Quantitation of HIV-1 in lymphoid tissueWe purified lymph node mononuclear cells (LNMC) from excisional biopsies and extracted (QIAmp; Qiagen) HIV-1 RNA, according to standard procedures. The RNA extracts were treated with 100 ng of DNase (Gibco) and then were reverse-transcribed in a solution containing 3 mM MgC12, 10 mM dithiothreitol, 50 mM Tris-HC1 (pH 8.3), 75 mM KC1, 0.5 mM each dNTP, 0.4 μM specific antisense primer (below), 200 U of Moloney murine leukemia virus RT (Gibco BRL), 40 U of RNA guard (Pharmacia), and 10 μL (∼1 μg) of RNA in a 25-μL reaction. The resultant cDNA (500 ng/PCR reaction) was amplified by PCR and was probed for HIV-1 gag sequences, using a liquid hybridization procedure [41, 42]. This assay can detect 1–5 copies of HIV-1 RNA per microgram of total RNA

PCR in situ hybridization for localization of HIV-1 DNA in tissue sectionsPreparation of lymph node sections, reagents, thermocycling, and hybridization conditions for PCR in situ hybridization were as described elsewhere [42 –44]. The PCR product was detected by in situ hybridization, using a cocktail of 3 HIV-1 gag–specific oligonucleotides labeled with digoxigenin-11–dUTP (Boehringer Mannheim). All 3 oligonucleotide probes were in sense orientation and were internal to the PCR primer binding sequences (SK102, 5′-GAGACCATCAATGAGGAAGCTGCAGAATGGGAT; SK19, 5′-ATCCTGGGATTAAATAAAATAGTAAGAATGTATAGCCCTAC; and SJB9I, 5′-CTGTTCCTGGTTTCCTTGGGAAATCTCTGA). Computerized image analysis was used to determine the percentage of positively staining cells in 10 representative regions of the lymph node under 10× power, as described elsewhere [2, 44]

Statistical methodsDescriptive statistics were used to summarize the data. Because the mean time from enrollment to therapy initiation was 12 days, time zero and 12 days after enrollment were defined as the therapy initiation dates for the treated and the delayed-treatment patients, respectively. To exclude conditions resulting from seroconversion-related immunosuppression [31], we included opportunistic and other conditions only after day 21 of antiretroviral therapy administration. For each individual, laboratory data values were interpolated between measurements. Overall trends by early- and delayed-treatment groups were characterized as pointwise medians and means of interpolated individual trajectories, respectively. The Wilcoxon&amp;rank sum test was used for comparison between the 2 groups. Estimation of CD4+ T cell slope over time used the mixed-effect model to account for the correlation of repeated measures within the same individual, in which the patient was the random effect [45]. All P values were calculated as 2-sided. All analyses were performed at the Fred Hutchinson Cancer Research Center (Seattle)

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Results

As shown in table 1, the demographic, clinical, and virologic data at enrollment were similar for the 20 treated patients and 47 delayed-treatment patients. Treated patients were followed up for a median of 98 weeks (range, 6–167 weeks); delayed-treatment patients were followed up for a median of 149 weeks (range, 4–322 weeks). Data for the first 78 weeks were included in this analysis, to allow for equal comparison between the treated and control groups. Genotypic analyses for resistance mutations were performed on the entry plasma isolates for all 20 treated patients and for 30 of 47 delayed-treatment patients. None of the 50 isolates tested had mutations associated with PI resistance. All isolates were wild type at position 184. One untreated patient had a mutation at codon 215 in the RT gene (T215F), and 2 treated patients had mutations K70R/T69N and T215D/M41L, which have been shown to confer reduced susceptibility to RT inhibitors. Both of the treated patients had rapid suppression of their plasma HIV-1 RNA levels, but the rates did not differ from those of the other treated patients (see below)

Virologic response to antiretroviral therapyAt a median of 7 weeks (95% confidence interval [CI], 3–8), all 20 treated patients receiving HAART achieved plasma HIV-1 RNA levels <500 copies/mL; at a median of 19 weeks (95% CI, 12–20), they had achieved <50 copies/mL (figure 1A ). Treated patients who continued to receive therapy maintained plasma HIV-1 RNA levels <50 copies/mL for the duration of follow-up. Three patients had transient (1 time point) increases in HIV-1 RNA <100 copies/mL at weeks 20, 32, and 44, respectively, after the initiation of therapy, with no apparent correlation with symptomatic intercurrent illnesses or vaccinations. Time to plasma HIV-1 RNA levels <50 copies/mL did not correlate with the time from onset of symptoms to the initiation of therapy, peak plasma HIV-1 RNA level, severity of seroconversion symptoms, or initial CD4+ T cell count (data not shown)

Figure 1
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Figure 1

Composite diagrams of plasma human immunodeficiency virus type 1 (HIV-1) RNA and total DNA in treated and delayed-treatment patients with primary HIV-1 infection. A Median titer of plasma HIV-1 RNA at the initiation of treatment (P=.001 for comparison of treated and delayed-treatment group after 6 weeks of therapy). B Median titer of viral DNA copies/106 CD4+ T cells in the treated and delayed-treatment patients (P=.002 at week 24). A and B No. of persons assayed at each time point is shown at the bottom of each panel. C No. and frequency of positive cultures in peripheral blood mononuclear cells (10×106 cells/culture) in both treated and delayed-treatment cohorts

Delayed-treatment patients had a median HIV-1 RNA plasma level of 7.04×105 copies/mL at baseline. At day 12 after enrollment (defined as day zero for the comparison), the median plasma HIV-1 RNA level was 3.8×105 copies/mL, which reflects the decrease in plasma viremia seen in very early HIV-1 infection, even without antiretroviral therapy. None of the delayed-treatment patients had plasma HIV-1 RNA levels <50 copies/mL during the 78 weeks. One patient began stavudine monotherapy 54 days after asymptomatic seroconversion and subsequently achieved plasma HIV-1 RNA levels <500 copies/mL. The virologic responses between treated and delayed-treatment patients became distinct after 6 weeks of therapy (figure 1A ), and the difference was statistically significant for all time points thereafter (P<.001). At week 24, the median plasma HIV-1 RNA level for delayed-treatment patients was 35,124 copies/mL (range, 316–229,172 copies/mL), compared with <50 copies/mL for the patients treated with combination therapy

Effect of therapy on proviral DNA and culturable virus in peripheral blood mononuclear cells (PBMC) and LNMCOther measures of HIV-1 replication also were suppressed by therapy, albeit not as completely as plasma HIV-1 RNA. HIV-1 DNA in PBMC decreased among delayed-treatment patients, from a median of 6.3×103 copies/106 CD4+ T cells at enrollment to 4.1×102 copies/106 CD4+ T cells at week 42 (figure 1B ). Within the first 24 weeks of therapy, viral DNA fell below the level of detection (<180 copies/106 CD4+ T cells) in 7 (35%) of 20 treated patients; however, viral DNA remained below the level of detection in only 1 of these 7 patients. In contrast, delayed-treatment patients showed gradually increasing levels of viral DNA during follow-up, with all measurements remaining above the level of detection for 18 (94.7%) of the 19 patients. Values for interpolated HIV-1 DNA at week 24 for treated versus delayed-treatment patients were significantly lower (P=.002; figure 1B ). Treatment also reduced the ability to isolate HIV-1 from PBMC. Of 71 viral cultures from treated patients after day 180, 14 (20%) were positive versus 116 (94%) of 123 cultures in delayed-treatment patients (P<.01; figure 1C )

Of the 20 treated patients approached for excisional inguinal lymph node biopsies, 5 consented. At the time of biopsy, between weeks 36 and 54 after onset of therapy, all patients had plasma HIV-1 RNA levels <50 copies/mL. We compared the levels of viral RNA in these 5 biopsy samples with those in the 7 biopsy samples from delayed-treatment patients who underwent biopsy at similar time points. HIV-1 RNA expression was lower in lymph nodes of all 5 treated versus delayed-treatment patients. However, all 5 treated patients had evidence of persistent HIV-1 transcription in their inguinal biopsy samples. A representative depiction is shown in figure 2. RT-PCR (figure 2A ) demonstrated the presence of HIV-1 gag RNA in LNMC at an average of 1 copy/104 cells in a treated patient. This compares with 1 copy/102 cells in a delayed-treatment patient (figure 2C ). Of interest, the frequency and distribution of HIV-1 DNA–positive cells, as determined by in situ PCR, showed no significant difference in viral DNA burden between the initially treated and delayed-treatment patients (10.8±1.3 vs. 11.6±1.0 per ×10 microscopic field, respectively; figure 2B 2D )

Figure 2
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Figure 2

Representative nested reverse transcription–polymerase chain reaction (PCR) and liquid hybridization strategy showing the presence of human immunodeficiency virus type 1 (HIV-1) gag RNA in lymph node mononuclear cells from a treated patient after 52 weeks of therapy and 24 weeks after plasma HIV-1 RNA suppression (A and B). A biopsy was performed on the node from the untreated patient at week 73, when the patient had a plasma HIV-1 RNA level of 15,854 copies/mL (C and D). Note in A that the intracellular RNA copy no. is low in the treated patient (∼1 copy/10,000 cells), yet it is indicative of continued viral gene expression in the presence of highly active antiretroviral therapy. In contrast, C shows much higher levels of viral gene expression in the untreated patient (∼1 copy/100 cells). Representative sections of inguinal lymph node from a treated (B) and untreated (D) patient show the frequency and distribution of HIV-1 DNA–positive cells, using in situ PCR. By quantitative microscopy, the frequency of HIV-1 DNA–positive cells is similar in the treated vs. untreated patient (anti–digoxigenin–alkaline phosphatase for HIV-1 gag RNA; bar, 100 μm)

Effect of combination antiretroviral therapy on CD4 + T cellsUsing a mixed-effects model to evaluate the trends in CD4+ T cell counts over the 78 weeks of follow-up, we observed a sustained increase of 12.5 cells/μL per month in treated patients, compared with a loss of 9.5 cells/μL per month in delayed-treatment patients (P<.001; figure 3). At week 78, the median increase in CD4+ T cell counts for treated patients was 195 cells/μL (absolute value, 845 cells/μL) over baseline. The rate of increase in CD4+ T cell count correlated with neither patient age nor time to plasma HIV-1 RNA suppression of <50 copies/L. At week 78, the median absolute CD4+ T cell count among delayed-treatment patients was 457 cells/μL, which was 178 cells/μL lower than values at enrollment

Figure 3
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Figure 3

Mean CD4+ T cell counts among human immunodeficiency virus–infected patients immediately treated with combination antiretroviral therapy and delayed-treatment patients (P<.01 for all time points depicted)

Progression to AIDS: frequency of opportunistic and nonopportunistic disease during follow-upDelayed-treatment patients had significantly more opportunistic and nonopportunistic diseases, and a higher proportion had rapid progression to AIDS (table 2; figure 4). During the 78 weeks of follow-up, 10 (21%) of 47 delayed-treatment patients experienced 20 discrete episodes of opportunistic infections versus 1 patient (who had discontinued therapy after 4 weeks) in the immediate, combination therapy group (P=.02). Among the delayed-treatment cohort, 12 oral or esophageal candidal infections and 8 cases of oral hairy leukoplakia were documented (table 2). Six (13%) of 47 delayed-treatment patients developed CD4+ T cell counts ⩽200 cells/μL within 78 weeks of follow-up, including 1 patient who developed a sustained CD4+ T cell count <200 cells/μL within 12 weeks of HIV-1 infection. Four of these 6 delayed-treatment therapy patients developed CD4+ T cell counts ⩽200 cells/μL before any definable opportunistic infection. None of the initially treated patients developed a CD4+ T cell count ⩽200 cells/μL during the initial 78 weeks of follow-up. Overall, 14 (30%) of the 47 initially untreated patients developed a class B or C opportunistic infection or CDC-defined AIDS during follow-up, compared with 1 (5%) of 20 in the immediate therapy group (P=.01; figure 4)

Figure 4
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Figure 4

Kaplan-Meier plot showing time to development of human immunodeficiency virus type 1 (HIV-1) infection or to CDC-defined class of opportunistic infection (OI) among initially treated and delayed-treatment HIV-1–infected patients (P=.01 for comparison)

Figure 5
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Figure 5

Frequency of clinical and laboratory (all grades) abnormalities among patients with primary human immunodeficiency virus infection treated with combination antiretroviral therapy. NA, not applicable

Table 1
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Table 1

Comparison of the demographic and enrollment clinical characteristics among patients with acute primary human immunodeficiency virus type 1 (HIV-1) infection who immediately received 3-drug therapy and those who were not treated immediately

Table 2
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Table 2

Frequency and type of opportunistic infections and progression to AIDS after acute primary human immunodeficiency virus infection among 20 treated and 47 untreated patients

A marked difference in the incidence of nonopportunistic conditions was noted in these 2 cohorts (table 3). Nineteen (40%) of the 47 delayed-treatment patients had bacterial pneumonia, bronchitis, or sinusitis during follow-up; 39 discrete respiratory infections were documented. Of 20 of the treated patients, 3 (15%) experienced 5 episodes of respiratory infections (relative risk [RR], 0.27; P=.009). Similar findings were seen with mucocutaneous conditions: treated patients experienced significantly fewer new diagnoses of genital or rectal warts, folliculitis, psoriasis, seborrheic dermatitis, and severe gingivitis (RR, 0.17; P<.001; table 3). Although both varicella zoster and herpes simplex virus reactivations also were reduced in the early- versus delayed-treatment cohorts, these differences did not reach statistical significance

Table 3
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Table 3

Frequency of respiratory and mucocutaneous conditions in the first 78 weeks after primary human immunodeficiency virus infection among treated and delayed-treatment patients

Adverse events and adherence to medicationsMinor adverse events attributable to antiretroviral therapy were seen in all treated patients (figure 5). All patients reported some degree of nausea within the first 2 weeks of therapy. Seven patients (35%) reported moderate nausea and vomiting that required a change from zidovudine to stavudine, and 2 patients (10%) were changed from zidovudine to stavudine therapy because of anemia. One patient discontinued indinavir because of recurrent nephrolithiasis at week 16. Periungual abnormalities of the great toe developed in 2 patients, one of whom required surgical intervention. Severe aminotransferase abnormalities were seen in 2 patients. One patient developed cervicodorsal fat deposition (“buffalo hump”) 21 months after therapy initiation

Adherence to the treatment regimen was monitored by pill counts and daily diaries. A mean 96% (range, 76%–100%) of doses were taken by patients. Four patients reported 100% adherence. Treatment was discontinued during the first year in 4 patients. One of the patients discontinued combination therapy after 4 weeks for nausea and fatigue; he developed oral candidiasis 3 weeks later. The second patient discontinued therapy at 52 weeks, and within 12 weeks, his plasma HIV-1 RNA level increased to 684 copies/mL, at which point he established a plateau for the next 12 months. He has remained well but has begun to experience a reduction in his CD4+ T cell count. Two additional patients discontinued therapy for personal reasons: one moved from the area and elected not to continue the treatment protocol, and the other was admitted to an in-patient substance-abuse rehabilitation center. Thus, although only 9 (45%) patients continued to follow the initial regimen, 16 (80%) were able to continue a 3-drug regimen that included a PI for the 78 week follow-up

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Discussion

Initiation of combination antiretroviral therapy at the time of diagnosis of primary HIV-1 infection produced significant virologic, immunologic, and clinical benefit in this cohort of patients with symptomatic primary HIV-1 infection. A treatment regimen consisting of 2 RT inhibitors and a PI resulted in prompt reductions in plasma HIV-1 RNA, 90% less frequent opportunistic infections (oral and esophageal candidiasis and oral hairy leukoplakia), and 70%–80% reduced frequency of respiratory and mucocutaneous conditions. More important, immediate treatment with combination antiretrovirals was protective against rapid progression to CDC Class B or C opportunistic infections or AIDS (defined by CD4+ T cell counts ⩽200 cells/μL). However, as demonstrated by a variety of techniques, initiation of therapy during primary infection did not prevent the establishment of viral latency or eradicate HIV-1 replication in any of the patients studied [46 –49]

This study also provides information on a number of questions raised about the initiation of therapy during acute HIV-1 infection. Early concerns about the use of antiretroviral therapy during acute HIV-1 infection questioned whether prompt responses could be achieved if therapy were initiated during a period of high viremia and whether initiation of therapy at this stage would result in the rapid emergence of viral resistance and subsequent virologic breakthrough. All the initially treated patients reported here, even those with plasma HIV-1 RNA levels >500,000 copies/mL at enrollment, achieved prompt and sustained virologic responses. One contributing factor to this prompt reduction in plasma viremia may have been the low frequency of drug resistance among the initially treated patients in the Seattle cohort. However, despite this susceptibility to antiretrovirals, eradication of HIV-1 from reservoirs in LNMC and PBMC was not achieved [6, 48 –51]. Similar to the finding of Zhang et al. [46], sequencing of viral DNA from lymph node monocyte/macrophage and resting cell reservoirs in our patients after the initiation of HAART during primary HIV-1 infection has not revealed the emergence of RT or PI resistance mutations. Thus, although additional studies need to be performed, this study demonstrates that excellent antiviral responses can be achieved with early combination antiretroviral therapy

Although plasma HIV-1 RNA levels were sustained below the limit of detection among patients who continued to receive combination therapy, levels of total HIV-1 DNA in CD4+ T cells and lymph node reservoirs were maintained, and low-level transcription of HIV-1 RNA in lymph node tissue could still be detected, even when therapy was initiated within days of the onset of seroconversion symptoms [6]. Perhaps the best in vivo demonstration of HIV-1 persistence, despite early initiation of therapy, was the increase in HIV-1 RNA and subsequent disease progression seen in both patients who elected to discontinue therapy but who continued to be followed up. The patient who discontinued therapy at 4 weeks developed oral candidiasis within 3 weeks, and the other patient subsequently had a CD4+ T cell count decline. Thus, at present, it appears prudent to continue antiretroviral therapy among patients with primary HIV-1 infection who have undetectable plasma HIV-1 RNA levels, particularly as sustained increases in their CD4+ T cell counts are observed (figure 3). Whether intermittent treatment interruptions would prevent the type of CD4+ T cell count declines that we saw with complete interruption is unclear [50, 51]

Although clinical benefits from early therapy were demonstrated, these benefits were accompanied by nearly universal drug-associated toxicities, which illustrates the importance of developing less toxic therapy [52 –56]. Although frequent regimen alterations were needed, it was possible to keep 80% of patients on potent aggressive antiretroviral regimens for the duration of the study. Long-term studies of the patients are ongoing. As reported in other populations, fasting lipid abnormalities appear to be increasing in these patients [54 –56]

Balancing these side effects of therapy are the clinical benefits seen in initially treated patients. Patients who continued therapy with combination antiretrovirals experienced no opportunistic infections or CDC-defined AIDS after initiation of therapy, which is an improved and consistent finding versus the effects of zidovudine monotherapy during primary HIV-1 infection [20, 21]. Although selection bias must be considered in interpreting these results, the high incidence of progressive disease seen in those patients who received delayed treatment is characteristic of symptomatic seroconverters referred to HIV-1 care centers [57 –59]

An interesting clinical benefit observed in this cohort was a 70%–80% reduction in nonherpetic mucocutaneous and respiratory conditions seen during the early course of HIV-1 infection. These data suggest that in vitro immunosuppressive effects [8 –10] seen with early HIV-1 infection appear to be operative in vivo; more detailed studies of the immunologic defects in HIV-infected persons may provide insight into the pathogenesis of psoriasis, seborrheic dermatitis, folliculitis, gingivitis, and other noninfectious complications of HIV-1 infection. These data also indicate that most early HIV-1 infections are not truly asymptomatic: 60% of the patients with HIV-1 infection in the Seattle cohort experienced infectious and immunologic complications within the first 78 weeks of HIV-1 infection

Clinical outcomes from therapeutic interventions ideally are evaluated in randomized, blinded trials; however, the widespread belief that early therapy might prove advantageous precluded a randomized study [11 –14]. All available data indicate that at enrollment, the virologic, clinical, and demographic characteristics were similar in the early-treatment and delayed-treatment cohorts. Hence, the clinical and virologic benefits observed in the initially treated patients are likely attributable to antiretroviral therapy rather than to undefined host or virologic differences between the 2 cohorts. White men who have sex with men comprised a majority of study patients in both cohorts, which reflects the demographics of the HIV-1 epidemic in Seattle. As adherence and frequency of drug resistance play an important role in clinical outcome of HIV-1 infection, studies in other populations, such as women and injection drug users, are warranted

In conclusion, initiation of potent antiretroviral therapy within 90 days of HIV-1 infection was associated with reduced HIV-1 in plasma and cellular compartments and with immune preservation, as evidenced by improved CD4+ T cell counts, decreased opportunistic infections, and decreased frequency of respiratory and mucocutaneous conditions. Rapid progression to AIDS also was averted. Side effects of combination therapy were common, modifications to therapy frequent, and low levels of viral replication evident in cellular and anatomic reservoirs. With intensive counseling and close follow-up, most patients were maintained on a potent antiretroviral regimen containing a PI. Better-tolerated regimens with higher potency are still needed, as are long-term studies to determine whether clinical benefits are sustained

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Acknowledgments

We are indebted to the patients who volunteered for this study and their medical care providers, to the University of Washington Retrovirology Laboratory for their dedication, and to Richard Donovan (Henry Ford Hospital) for performing the genotyping assays. Denny Guang Yeu Lee (Fred Hutchinson Cancer Research Center [FHRC], Seattle, WA) was instrumental in preliminary data analyses, and Yijian Huang (FHRC) conducted statistical analyses. We also thank Merck Research Laboratories for financial support and both Merck and Glaxo Wellcome for their support in providing medication. A special thank you is extended to Nancy Coomer (FHRC) for her tireless work on the manuscript

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Footnotes

  • ↵Presented in part: 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, 24–27 September 1998 (abstract I-57); 39th ICAAC, San Francisco, 26–29 September 1999 (abstract 684)

    All study protocols were approved by the University of Washington Institutional Review Board, and all participants gave informed consent for enrollment and follow-up procedures

    Financial support: Merck; Glaxo Wellcome; National Institutes of Health (AI-41535; AI-31448 to Center for AIDS Research, University of Washington; AI-07140, training grant to M.M.B.)

  • ↵Present affiliations: Glaxo SmithKline, Research Triangle Park, North Carolina (M.M.B.); Department of Medicine, University of Minnesota, Minneapolis (T.S.)

  • Received March 16, 2000.
  • Revision received February 2, 2001.
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References

  1. ↵
    1. Pantaleo G,
    2. Cohen O,
    3. Schacker T,
    4. et al
    . Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: implications for antiviral therapy. Nat Med 1998;4:341-5.
    CrossRefMedlineWeb of Science
  2. ↵
    1. Haase AT,
    2. Henry K,
    3. Zupancic M,
    4. et al
    . Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 1996;274:985-9.
    Abstract/FREE Full Text
  3. ↵
    1. Chun TW,
    2. Carruth L,
    3. Finzi D,
    4. et al
    . Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997;387:183-8.
    CrossRefMedline
  4. ↵
    1. Wong JK,
    2. Hezareh M,
    3. Gunthard HF,
    4. et al
    . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997;278:1291-5.
    Abstract/FREE Full Text
  5. ↵
    1. Finzi D,
    2. Hermankova M,
    3. Pierson T,
    4. et al
    . Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997;278:1295-1300.
    Abstract/FREE Full Text
  6. ↵
    1. Chun TW,
    2. Engel D,
    3. Berrey MM,
    4. Corey L,
    5. Fauci T
    . Early establishment of a pool of latently infected resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci USA 1998;95:8869-73.
    Abstract/FREE Full Text
  7. ↵
    1. Musey L,
    2. Hughes J,
    3. Schacker T,
    4. Shea T,
    5. Corey L
    . Cytotoxic T cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997;337:1267-74.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Connors M,
    2. Kovacs JA,
    3. Krevat S,
    4. et al
    . HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997;3:533-40.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Gorochov G,
    2. Neumann UA,
    3. Kereveur A,
    4. et al
    . Perturbations of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 1998;4:215-21.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Pantaleo G,
    2. Demarest JF,
    3. Schacker T,
    4. et al
    . The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc Natl Acad Sci USA 1997;94:254-8.
    Abstract/FREE Full Text
  11. ↵
    1. Ho DD
    . Toward HIV eradication or remission: the tasks ahead. Science 1998;280:1866-7.
    Abstract/FREE Full Text
  12. ↵
    1. Walker BD,
    2. Basgoz N
    . Treat HIV-1 infection like other infections: treat it. JAMA 1998;280:91-3.
    FREE Full Text
  13. ↵
    1. Deeks S,
    2. Volberding P
    . Antiretroviral therapy for HIV infection: promises and problems. JAMA 1998;279:1343-4.
    FREE Full Text
  14. ↵
    1. Walker BD,
    2. Goulder PJ
    . AIDS. Escape from the immune system. Nature 2000;407:313-4.
    CrossRefMedline
  15. ↵
    1. Soudeyns H,
    2. Campi G,
    3. Rizzardi P,
    4. et al
    . Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor β chain repertoire and reduces the level of T-cell oligoclonality. Blood 2000;95:1743-51.
    Abstract/FREE Full Text
  16. ↵
    1. Perrin L,
    2. Rakik A,
    3. Yerly S,
    4. et al
    . Combined therapy with zidovudine and L-697,661 in primary HIV infection. AIDS 1996;10:1233-7.
    MedlineWeb of Science
  17. ↵
    1. Perrin L,
    2. Yerly S
    . Acute HIV infection. J Biol Regul and Homeost Agents 1995;9:95-9.
  18. ↵
    1. Lafeuillade A,
    2. Poggi C,
    3. Tamalet C,
    4. Profizi N,
    5. Tourres C
    . Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis 1997;175:1051-5.
    Abstract/FREE Full Text
  19. ↵
    1. Tindall B,
    2. Gaines H,
    3. Imrie A,
    4. et al
    . Zidovudine in the management of primary HIV-1 infection. AIDS 1991;5:477-84.
    CrossRefMedlineWeb of Science
  20. ↵
    1. Kinloch-de Loes S,
    2. Hirschel BJ,
    3. Hoen B,
    4. et al
    . Zidovudine versus placebo in primary HIV infection: a randomized study. N Engl J Med 1995;333:408-13.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Kinloch-de Loes S,
    2. Perneger TV
    . Primary HIV infection: follow-up of patients initially randomized to zidovudine or placebo. J Infect 1997;35:111-6.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Smith D,
    2. Berrey MM,
    3. Robertson M,
    4. et al
    . Virological and immunological effects of combination antiretroviral therapy during primary HIV-1 infection. J Infect Dis 2000;182:950-4.
    Abstract/FREE Full Text
  23. ↵
    1. Hammer SM,
    2. Squires KE,
    3. Hughes MD,
    4. et al
    . A controlled trial of two nucleoside analogs plus indinavir in persons with human immunodeficiency virus infection and CD4 counts of less than 200 per cubic millimeter or less. ACTG Group 320 Study Team. N Engl J Med 1997;337:725-33.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Gulick RM,
    2. Mellors JW,
    3. Havlir D,
    4. et al
    . Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337:734-9.
    CrossRefMedlineWeb of Science
  25. ↵
    1. Chene G,
    2. Binquet C,
    3. Moreau JF,
    4. et al
    . Changes in CD4+ cell count and the risk of opportunistic infection or death after highly active antiretroviral treatment. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine. AIDS 1998;12:2313-20.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Cameron DW,
    2. Heath-Chiozzi M,
    3. Danner S,
    4. et al
    . Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Advanced HIV Disease Ritonavir Study Group. Lancet 1998;351:543-9.
    CrossRefMedlineWeb of Science
  27. ↵
    1. Carpenter CC,
    2. Fischl MA,
    3. Hammer SM,
    4. et al
    . Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society–USA panel. JAMA 1997;277:1962-9.
    Abstract/FREE Full Text
  28. ↵
    1. Schacker T,
    2. Collier AC,
    3. Hughes JP,
    4. Shea T,
    5. Corey L
    . Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996;125:257-64.
    Abstract/FREE Full Text
  29. ↵
    1. Schacker T,
    2. Hughes JP,
    3. Shea T,
    4. Coombs RW,
    5. Corey L
    . Biological and virologic characteristics of primary HIV infection. Ann Intern Med 1998;128:613-20.
    Abstract/FREE Full Text
  30. ↵
    1. Vanhems P,
    2. Lambert J,
    3. Cooper DA,
    4. et al
    . Severity and prognosis of acute human immunodeficiency virus type 1 illness: a dose-response relationship. Clin Infect Dis 1998;26:323-9.
    Abstract/FREE Full Text
  31. ↵
    1. Malhotra U,
    2. Berrey MM,
    3. Huang Y,
    4. et al
    . Effect of combination antiretroviral therapy on T cell immunity in acute human immunodeficiency virus type 1 infection. J Infect Dis 2000;181:121-31.
    Abstract/FREE Full Text
  32. ↵
    1. Sande MA,
    2. Carpenter CC,
    3. Cobbs CG,
    4. Holmes KK,
    5. Sanford JP
    . Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art panel on anti-retroviral therapy for adult HIV-infected patients. JAMA 1993;270:2583-9.
    Abstract/FREE Full Text
  33. ↵
    1. Division of AIDS (DAIDS) Regulatory Operations Center (ROC)
    . Rockville, MD: ROC, SAE office; 1998. Serious adverse events (SAE) reporting manual for AIDS Clinical Trials Groups (AACTG and PACTG), Community Programs for Clinical Research on AIDS (CPCRA), and Intramural Research Program (IRP).
  34. ↵
    1. Centers for Disease Control and Prevention
    . 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Report 1992;41((RR-17)):1-19.
    Medline
  35. ↵
    1. Brambilla D,
    2. Leung S,
    3. Lew J,
    4. et al
    . Absolute copy number and relative change in determinations of human immunodeficiency virus type 1 RNA in plasma: effect of an external standard on kit comparisons. J Clin Microbiol 1998;36:311-4.
    Abstract/FREE Full Text
  36. ↵
    1. Erali M,
    2. Hillyard DR
    . Evaluation of the ultrasensitive Roche Amplicor HIV-1 monitor assay for quantitation of human immunodeficiency virus type 1 RNA. J Clin Microbiol 1999;37:792-5.
    Abstract/FREE Full Text
  37. ↵
    1. Campbell TB,
    2. Sevin A,
    3. Coombs RW,
    4. et al
    . Changes in human immunodeficiency virus type 1 load during mobilization and harvesting of hemopoietic progenitor cells. Adult AIDS Clinical Trials Group 285 Study Team. Blood 2000;95:48-55.
    Abstract/FREE Full Text
  38. ↵
    1. Demeter LM,
    2. D’Aquila R,
    3. Aquila R,
    4. Weislow O,
    5. et al
    . Interlaboratory concordance of DNA sequence analysis to detect reverse transcriptase mutations in HIV-1 proviral DNA. ACTG Sequence Working Group. AIDS Clinical Trials Group. J Virol Methods 1998;75:93-104.
  39. ↵
    1. Salomon H,
    2. Wainberg MA,
    3. Brenner B,
    4. et al
    . Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact of injecting drug use. Investigators of the Quebec Primary Infection Study. AIDS 2000;14:F17-23.
    CrossRefMedlineWeb of Science
  40. ↵
    1. Marschner IC,
    2. Mayers DL,
    3. Erice A,
    4. et al
    . Standardized peripheral blood mononuclear cell culture assay for zidovudine susceptibility testing of clinical human immunodeficiency virus type 1 isolates: effect of reducing the numbers of replicates and concentrations. J Clin Microbiol 1997;35:756-8.
    Abstract/FREE Full Text
  41. ↵
    1. Yoshimura FK,
    2. Diem K,
    3. Learn GH,
    4. Riddell S,
    5. Corey L
    . Intrapatient sequence variation of the gag gene of human immunodeficiency virus type 1 plasma virions. J Virol 1996;70:8879-87.
    Abstract/FREE Full Text
  42. ↵
    1. Brodie SJ,
    2. Lewinsohn DA,
    3. Patterson BK,
    4. et al
    . In vivo migration and function of transferred HIV-1–specific cytotoxic T cells. Nat Med 1999;5:34-41.
    CrossRefMedlineWeb of Science
  43. ↵
    1. Brodie SJ,
    2. Wilson WC,
    3. O’Hearn PM,
    4. Hearn PM,
    5. Muthui D,
    6. Diem K
    . The effects of pharmacologic and lentivirus-induced immunosuppression on orbivirus pathogenesis: assessment of blood monocytes and tissues by in situ hybridization and reverse transcription in situ PCR. J Virol 1998;72:5599-609.
    Abstract/FREE Full Text
  44. ↵
    1. Brodie SJ,
    2. Bardsley KD,
    3. Mecham JO,
    4. Diem K,
    5. Norelius SE
    . Epizootic hemorrhagic disease: analysis of tissues by amplification and in situ hybridization reveals widespread orbivirus infection at low copy number. J Virol 1998;72:3863-71.
    Abstract/FREE Full Text
  45. ↵
    1. Laird NM,
    2. Ware JH
    . Random effects model for longitudinal data. Biometrics 1982;38:963-74.
    CrossRefMedlineWeb of Science
  46. ↵
    1. Zhang L,
    2. Ramratnam B,
    3. Tenner-Racz K,
    4. et al
    . Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. New Engl J Med 1999;340:1605-13.
    CrossRefMedlineWeb of Science
  47. ↵
    1. Chun TW,
    2. Engel D,
    3. Mizell SB,
    4. et al
    . Effect of interleukin-2 administration on the pool of latently infected, resting CD4+ T cells in HIV-1 infected patients receiving highly active antiretroviral therapy. Nat Med 1999;5:651-5.
    CrossRefMedlineWeb of Science
  48. ↵
    1. Furtado MR,
    2. Callaway DS,
    3. Phair JP,
    4. et al
    . Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. New Engl J Med 1999;340:1614-22.
    CrossRefMedlineWeb of Science
  49. ↵
    1. Wong JK,
    2. Hezareh M,
    3. Gunthard HF,
    4. et al
    . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997;278:1291-300.
    Abstract/FREE Full Text
  50. ↵
    1. Lori F,
    2. Lewis MG,
    3. Zu J,
    4. et al
    . Control of SIV rebound through structured treatment interruptions during early infection. Science 2000;290:1591-3.
    Abstract/FREE Full Text
  51. ↵
    1. Rosenberg ES,
    2. Atfeld M,
    3. Poon SH,
    4. et al
    . Immune control of HIV-1 after early treatment of acute infection. Nature 2000;407:523-6.
    CrossRefMedline
  52. ↵
    1. Viraben R,
    2. Aquilina C
    . Indinavir-associated lipodystrophy. AIDS 1998;12:F37-39.
    MedlineWeb of Science
  53. ↵
    1. Carr A,
    2. Samaras K,
    3. Burton S,
    4. et al
    . A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998;12:F51-55.
    CrossRefMedlineWeb of Science
  54. ↵
    1. Carr A,
    2. Samaras K,
    3. Chisolm DJ,
    4. Cooper DA
    . Pathogenesis of HIV-1 protease inhibitor–associated peripheral lipodystrophy, hyperlipidemia, and insulin resistance. Lancet 1998;351:1881-3.
    CrossRefMedlineWeb of Science
  55. ↵
    1. Miller KD,
    2. Jones E,
    3. Yanovski HA,
    4. Shankar R,
    5. Feuerstain I
    . Visceral abdominal–fat accumulation associated with use of indinavir. Lancet 1998;351:871-5.
    CrossRefMedlineWeb of Science
  56. ↵
    1. Lo JC,
    2. Mulligan K,
    3. Tai VW,
    4. Algren H,
    5. Schambelan M
    . “Buffalo hump” in men with HIV-1 infection. Lancet 1998;351:867-70.
    CrossRefMedlineWeb of Science
  57. ↵
    1. Veugelers PJ,
    2. Kaldor JM,
    3. Strathdee SA,
    4. et al
    . Incidence and prognostic significance of symptomatic primary human immunodeficiency virus type 1 infection in homosexual men. J Infect Dis 1997;176:112-7.
    Abstract/FREE Full Text
  58. ↵
    1. Keet IPM,
    2. Krijnen P,
    3. Koot M,
    4. et al
    . Predictors of rapid progression to AIDS in HIV-1 seroconverters. AIDS 1993;7:51-7.
    MedlineWeb of Science
  59. ↵
    1. Pederson C,
    2. Lindhardt BO,
    3. Jensen BL,
    4. et al
    . Clinical course of primary HIV infection: consequences for subsequent course of infection. BMJ 1989;299:154-7.
    Abstract/FREE Full Text
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