急性HIV感染

 

 

Vivian Levy, M.D.

Stanford University, Division of Infectious Diseases

San Mateo Medical Center, Clinical Trials and Research

222 West 39th Avenue

San Mateo, CA 94403

Phone: (650)573-2385, Fax: (650) 573-2474

E-mail: vlevy@stanford.edu

 

Robert M. Grant, M.D., M.P.H

Associate Investigator

Gladstone Institute of Virology and Immunology

Associate Professor of Medicine

University of California, San Francisco

PO Box 419200

San Francisco, CA 94141-9100

Phone:(415)695-3809, Fax:(415)826-8449

E-mail: rgrant@itsa.ucsf.edu

 

译者：曹玮 博士

   北京协和医院 内科

   Email: weic1981@gmail.co

 

审阅者：黄晓婕主治医师

     北京佑安医院感染

 

     吴昊 教授

     北京佑安医院感染科

 

 

Diagnosis of Acute HIV Infection

急性HIV感染的诊断

               Acute HIV infection, defined as the time from virus entry to completion of detectable antibody responses to HIV, is a unique opportunity for therapeutic intervention in selected patients. Acute infection is followed by early stage infection, the interval between seroconversion and the establishment of the viral load set point, which usually occurs 6-12 months after infection (25).

　　急性HIV感染，是指从病毒入侵到机体针对HIV产生可检测抗体的这段时间，是某些患者中进行治疗性干预的独特时机。在急性感染后进入感染早期，即从血清转换到病毒载量调定点确立的时间，通常为感染后6-12个月 (25)。

               About 40% to 90% of persons with newly acquired HIV infection will have symptoms of an acute viral infection, such as fever, rash, and myalgias (Table 1) (19, 24, 36, 40, 46). The syndrome may last from a few days to more than 10 weeks, but usually lasts less than two weeks. Acute HIV infection should be considered in persons presenting with these symptoms 2-6 weeks after a possible HIV exposure. (24, 40) or with this acute retroviral syndrome accompanied by a sexually transmitted disease (48).

　　约40%至90%的新发HIV感染者具有急性病毒性感染的症状，如发热、皮疹和肌痛（表1）(19, 24, 36, 40, 46)。这些症状可能会持续数天乃至10周以上，但通常持续时间不超过两周。在可能的HIV暴露后出现上述症状达2-6周者(24, 40)，或急性逆转录病毒综合征同时伴有性传播疾病者(48)，应考虑其急性HIV感染的可能性。

               HIV infection is followed by a series of events with variable timing (4, 35). The initial post-exposure period, which occurs after infection but before the development of viremia, typically lasts 4-20 days. Because plasma HIV RNA can be detected for about 3-4 days before HIV p24 antigen, plasma viremia is the most sensitive means of diagnosing acute HIV infection (22). Although false-positive plasma HIV RNA levels can occur, the levels are usually lower (<3000 copies/ml) than in true positives (19) where peak viremia can reach levels of several million viral copies.

　　HIV感染后不同时期会发生一系列事件(4, 35)。暴露后初始阶段介于感染之后、病毒血症产生之前，通常持续4-20天。由于血浆HIV RNA的检测时间比HIV p24抗原早3-4天，血浆病毒血症是诊断急性HIV感染最为敏感的方法(22)。尽管可能会出现血浆HIV RNA水平假阳性，其值(<3000 拷贝/ml)也通常低于真阳性，后者病毒血症的峰值可达到数百万病毒拷贝水平。

               Less sensitive serologic assays can be used to confirm the diagnosis of HIV infection. Although enzyme immunoassay (EIA) tests used for blood screening can detect antibodies about one week after the initial appearance of plasma viremia, they may not be available in all laboratories. The more widely available EIA tests typically become positive one to two weeks after plasma viremia. Western blot serological assays begin to develop detectable bands about two weeks after plasma viremia.

        灵敏度较低的血清测定可用于确诊HIV感染。虽然用于血液筛查的酶联免疫测定（EIA）检测能够在血浆病毒血症首次出现后约1周时检测到抗体，但并非所有实验室都能使用EIA。使用最广泛的EIA检测通常在血浆病毒血症后一至两周变为阳性。血浆病毒血症出现约两周后，Western印迹血清学测定开始出现可检测的条带。

Benefits of Treatment During Acute HIV Infection

急性HIV感染期治疗的收益

               Currently, there is no evidence from human studies that antiretroviral therapy begun during acute infection decreases clinical progression or alters the clinical course of HIV compared with effective therapy begun later in disease. There are several potential benefits to instituting treatment during acute HIV infection: (1) reducing the symptoms associated with acute infection, (2) delaying progression to advanced immunodeficiency, (3) preserving HIV-specific immunity, (4) limiting the development of HIV diversity, and (5) decreasing the likelihood of HIV transmission when viral titers are high.

        迄今为止，人类研究中尚无证据表明，与疾病晚期开始有效抗病毒治疗相比，在急性感染期启动抗逆转录病毒治疗能够延缓临床进展或改变HIV的临床进程。在急性HIV感染期开始抗病毒治疗有以下潜在益处：（1）减轻急性感染的伴随症状，（2）延缓向严重免疫缺陷的进展，（3）保护HIV特异性免疫应答，（4）限制HIV产生变异，以及（5）降低病毒较高时HIV的传播率。

Reducing the Symptoms Associated with Acute Infection    

减轻急性感染的伴随症状

               The syndrome of acute HIV infection is usually self-limited and often escapes identification during clinical evaluation. However, some people with primary infection continue to experience symptoms for several months. These symptoms, including fever, rash, headache, and even oral thrush, can be prevented by antiretroviral therapy (3, 26). The subset of acutely infected persons with more severe or prolonged acute symptoms and persons with higher viral loads 6-12 months following resolution of the acute infection (higher viral set points) are more likely to be rapid HIV progressors (8, 13, 31).

        急性HIV感染的症状通常为自限性，在临床评估时往往被忽略。然而，某些原发感染者的症状可持续数月。抗逆转录病毒治疗可以控制这些症状，包括发热、皮疹、头痛，甚至鹅口疮 (3, 26)。急性期症状更严重或持续时间较长的急性感染者，以及急性感染期过后6-12个月时病毒载量较高的患者（病毒调定点较高），成为HIV快速进展者的可能性较大(8, 13, 31)。

Delaying Progression to Advanced Immunodeficiency

延缓向严重免疫缺陷的进展

               Cohort studies have suggested viral loads in acutely treated subjects rebound to lower levels than in untreated subjects (16, 39). Two other cohort studies of seroconverters treated during acute infection found viral set points were not significantly lower compared with seroconverters from earlier natural history cohorts (14, 33).

        队列研究提示，急性期治疗患者的病毒载量反弹水平低于不治疗人群(16, 39)。另外两组对血清转换者的急性感染期治疗队列研究则发现，其病毒调定点与血清转换早期自然病程队列相比并无显著降低(14, 33)。

Preservation of Immune Responses         

保护免疫应答      

               HIV-specific cell-mediated immune responses may be preserved in subjects treated prior to seroconversion (37, 39). Within six months of infection, CD4+ cells lose their ability to proliferate in response to HIV antigens (42). This is most likely because activated cells are infected and killed by viral replication and T cell activation (12). Antiretroviral therapy begun after chronic HIV viremia can restore immune responses to a wide variety of antigens but cannot re-establish anti-HIV proliferative responses, probably because clones of CD4+ T cells that recognize HIV antigens are exhausted (1, 2, 12, 44).

        血清转换前接受治疗的患者体内可能保留了HIV特异性细胞介导免疫应答(37, 39)。在感染后6个月内，CD4+细胞丧失了针对HIV抗原的增殖能力(42)。其最大可能的解釋是由于活化的细胞被感染，并在病毒复制和T细胞活化下被杀死(12)。慢性HIV血症后开始的抗逆转录病毒治疗能够重建对多种抗原的免疫应答，却不能重建抗HIV的增殖性应答，可能是由于识别HIV抗原的CD4+ T细胞克隆耗竭所致(1, 2, 12, 44)。

               HIV-specific CD8+ cytotoxic T lymphocytes detectable early after infection are strongly associated with control of viremia in acute and established infection (29). Epitopes targeted during acute infection often differ from those recognized during chronic infection (28). HIV specific CD4+ and CTL proliferative responses were found in both treated and untreated subjects during the first 18 months of infection but were markedly increased in treated subjects who maintained virologic control (27).

        感染后早期即可检测到HIV特异性CD8+ 细胞毒性T淋巴细胞，它与急性及慢性感染中病毒血症的控制显著相关(29)。急性感染期靶定的表位与慢性感染中识别的表位常不相同(28)。感染后的前18个月内，在治疗和不治疗的患者中均可检测到HIV特异性CD4+ 和CTL增殖应答，但该应答在持续病毒学控制的治疗患者体内显著增高(27)。

Limiting Viral Evolution

限制病毒进化                   

               The natural history of HIV evolution indicates that an initially homogenous virus population diversifies during the course of infection (9, 10, 41, 53). If the extent of viral diversity can be limited early in infection, variants with the ability to escape from host immunity or antiretroviral therapy are theoretically less likely to emerge.

        HIV进化的自然史表明，起初同质的病毒种群在感染过程中产生了进化(9, 10, 41, 53)。如果能在感染早期控制病毒的进化程度，理论上而言，能降低出现逃逸宿主免疫系统或药物的变异株的可能性。

Decreasing Transmission

降低传播    

               Recently infected persons may be particularly infectious, in part because of the high viral loads observed in primary viremia and because they may continue the risky behavioral patterns that led to their infection (38, 52). Treatment clearly decreases transmission from mothers to newborns (5). It also has been demonstrated in observational studies to decrease rates of sexual transmission (34), perhaps because viral load in genital secretions is markedly suppressed during therapy (18, 47).

        新近感染人群的传染性很强，其部分原因在于原发病毒血症具有很高病毒载量，而这些人群又很可能延续导致其感染的危险行为模式(38, 52)。治疗能明确降低母亲对新生儿的传播(5)。观察性研究也已证实治疗能够降低性传播的几率(34)，可能是由于治疗显著抑制了生殖道分泌物中的病毒载量(18, 47)。

Possible Risks of Early Treatment

早期治疗的可能风险

               There is no evidence that earlier treatment is associated with a higher likelihood of virus eradication (32). The mutational capacity of a rapidly replicating virus in acute HIV infection makes adherence critical to the success of acute HIV treatment. Reduced adherence or prolonged use of certain drug combinations may promote HIV drug resistance and limit drug options for future therapy. In addition to risks of antiretroviral resistance, there is a risk of serious toxicities with current therapy ("Complications of Antiretroviral Therapy").

        尚无证据表明早期治疗清除病毒的可能性更大(32)。急性HIV感染中迅速复制病毒的突变能力，使得依从性对于急性HIV治疗的成功极为关键。依从性下降或应用某种药物组合时间过长，可能会导致HIV耐药，从而限制今后治疗药物的选择。除了抗逆转录病毒耐药性风险以外，目前的治疗方案仍存在发生严重毒性的风险（“抗逆转录病毒治疗的并发症”）。

Transmitted Drug Resistance       

耐药性的传播

               About 10% of recently infected persons in North America and Europe exhibit primary resistance to at least one drug class, and about 5% are infected with viruses having genotypic evidence of resistance to at least two drug classes (17, 30, 43). Primary resistance poses a difficult clinical problem because the antiretroviral history of the source of infection is often unavailable. Resistance testing prior to initiating therapy should be done in North America and Europe, where the highest rates of primary drug resistance have been reported (11, 23, 49) . Clinicians should consider initiating therapy at once in these cases and revising the regimen when resistance test results are available.

        北美及欧洲新发感染人群中约10%对至少一类药物原发耐药，约有5%人群病毒的基因型检测显示对至少两类药物耐药性(17, 30, 43)。原发性耐药成为棘手的临床难题，通常不能获得感染源的抗逆转录病毒治疗史。在北美及欧洲等原发性耐药报道率高的地区，开始治疗前应当进行耐药性检测(11, 23, 49)。在这些情况下，医生应考虑立即开始治疗，并在得到耐药性检测结果后对治疗方案进行调整。

               Genotypic testing is likely to be the most sensitive method of detecting resistance because, unlike phenotypic tests, it can identify minority populations and transitional mutations. For example, T215C and T215D are common mutations resulting from T215Y and T215F back mutation. These mutations do not cause phenotypic resistance but suggest that T215Y or T215F may have been transmitted (15, 51).

        基因型检测可能是检测耐药性最敏感的方法，因为它与表型检测不同，能鉴定少数种群与过渡型突变。例如，T215C和T215D是由T215Y和T215F反向突变而导致的常见突变。这些突变不会导致表型耐药，但会提示可能传播了T215Y或T215F (15, 51)。

               Primary drug resistance may lengthen the time required to attain viral suppression or even prevent a response to treatment and lead to the development of additional drug resistance (20, 21). Subjects may eventually achieve virologic suppression, probably as a result of agents in the combination regimen to which the virus remains susceptible (30, 50). Primary resistance to multiple classes of drugs might best be managed by delaying therapy in order to identify the "set-point" or steady-state level of viremia. In some untreated subjects with a multidrug-resistant infection, the viral load after primary viremia is low and therapy may not be necessary.

        原发耐药可能会延长达到病毒抑制所需的时间，甚或影响治疗应答并导致产生其他药物的耐药(20, 21)。这些患者最终仍可达到病毒学抑制，可能是由于联合方案中仍含有敏感的药物(30, 50)。对多类药物原发耐药的最好处理方法，可能是延迟治疗时间以鉴定病毒血症的“调定点”或稳态水平。在某些具有多重耐药感染的不治疗人群中，原发病毒血症后的病毒载量很低，可能并不需要治疗。

Selection of Antiretroviral Drugs During Acute HIV Infection         

急性HIV感染中抗逆转录病毒药物的选择  

               There are no clinical trials of different HAART regimens in patients with acute HIV infection. Therefore most clinicians follow the guidelines outlined in the chapter on treating the previously untreated patient.

        尚无临床试验对急性HIV感染期使用不同HAART方案进行研究。因此，大多数临床医生遵从初治病人治疗章节中列出的指南。

               However, considering the increasing risk of transmitted drug resistance, it would not be unreasonable to choose one of the more aggressive regimens such as two NRTIs and a dual PI or three NRTIs and an NNRTI. Caution should be taken when beginning treatment for acute infection with an NNRTI. Class resistance to NNRTIs is suspected to be the most common type of primary drug resistance. Among NNRTIs, nevirapine is likely not an appropriate choice for empiric treatment of acute infection as it is associated with a higher incidence of serious hepatic and cutaneous toxicities compared to efavirenz (11). Nevirapine hepatic toxicity is more likely to occur in women with CD4+ T cell counts > 250 cells/mm3 and men with CD4+ T cell counts > 400 cells/mm3 pre-nevirapine use (7, 11). If susceptibility test results become available the treatment regimen can either be simplified or modified according to the results of these tests. The institution of antiretroviral therapy during acute HIV infection does not commit the patient to lifelong therapy; although treatment may be continued indefinitely if well tolerated. Therapy may be discontinued after adequate viral suppression has been achieved until guidelines warrant its reinstitution. Most clinicians who elect to treat acute HIV infection will extend the treatment for the first 6 months after seroconversion (25).

        然而，考虑到耐药性传播的风险，选择最强效方案不失其合理性，如2种NRTI药物＋1种增强的PI，或3种NRTI和1种NNRTI。当应用含NNRTI方案开始治疗急性感染时应警惕。NNRTI类药物的耐药被认为是原发性耐药中最常见类型。在NNRTI中，奈韦拉平不适用与急性感染的经验性治疗，因为与依非韦仑相比该药引发严重肝毒性和皮疹的风险显著增高(11)。用药前CD4+ T细胞计数>250细胞/mm3的女性患者和CD4+ T细胞计数>400细胞/mm3的男性患者，发生奈韦拉平肝毒性的可能性最大(7, 11)。如能进行敏感性检测，应根据这些检测的结果简化或修订治疗方案。在急性HIV感染期间启动抗逆转录病毒治疗，并不意味着患者必须进行终生治疗；但如果耐受良好可以继续无限期治疗。在达到适当的病毒抑制后可以中断治疗，除非指南说明应当重新启用。大多数临床医生会選擇启动对急性HIV感染的治疗並延續其洽疗至至血清转换后6个月(25)。

Treatment Interruptions Following the Treatment of Acute HIV Infection

急性HIV感染治疗后的治疗中断

               Intermittent interruption of therapy is not currently recommended practice, but is an active area of investigation. Treatment interruptions may serve to enhance HIV immune responses by providing bursts of viral antigen followed by viral suppression with drugs that spare the proliferating CD4+ cells from direct and indirect viral-mediated destruction (39). Treatment interruptions, however, may render HIV-specific CD4+ T cells vulnerable to the infection and destruction by HIV (12). Finally, it is possible that drug resistance will emerge more rapidly in subjects with repeated cycles of interrupted therapy.

        间断性治疗并非目前推荐之举，却是研究热点之一。间断治疗可能会增强HIV免疫应答，通过在大量病毒抗原释放后药物抑制病毒繁殖，可能可以避免增殖中的CD4+ 细胞遭受病毒的破坏(39)。然而治疗中断可能会使HIV特异性CD4+ T细胞易感并被HIV破坏(12)。最后，在接受周期性反复的间断治疗患者中，耐药性的产生可能会更快。

 

Tables and Figures

Table 1. Symptoms and Findings Associated with Acute HIV Infection

Sign or Symptom

Frequency (%)*

Fever

77 – 96

Adenopathy

48 – 74

Pharyngitis

43 – 70

Rash

51 - 70

Myalgias / arthralgias

54 – 60

Headache

32 – 57

Nausea / vomiting

24 – 58

Night sweats

22 – 51

Weight loss

13 – 69

Oral candidiasis

5 – 17

*Based on data from 588 patients in five studies (6, 19, 36, 40, 45).

表格和附图

 表1. 急性HIV感染的伴随症状和体征

症状或体征

发生率 (%)*

发热

77 – 96

淋巴结肿大

48 – 74

咽炎

43 – 70

皮疹

51 - 70

肌痛/关节痛

54 – 60

头痛

32 – 57

恶心/呕吐

24 – 58

盗汗

22 – 51

体重减轻

13 – 69

口腔念珠菌病

5 – 17

*根据五项研究中588名患者的研究数据 (6, 19, 36, 40, 45)。

 

REFERENCES

参考文献

1. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112-6. [PubMed]

2. Bart PA, Rizzardi GP, Tambussi G, Chave JP, Chapuis AG, Graziosi C, Corpataux JM, Halkic N, Meuwly JY, Munoz M, Meylan P, Spreen W, McDade H, Yerly S, Perrin L, Lazzarin A, Pantaleo G. Immunological and virological responses in HIV-1-infected adults at early stage of established infection treated with highly active antiretroviral therapy. AIDS 2000;14:1887-97. [PubMed]

3. Berrey MM, Schacker T, Collier AC, Shea T, Brodie SJ, Mayers D, Coombs R, Krieger J, Chun TW, Fauci A, Self SG, Corey L. Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS. J Infect Dis 2001;183:1466-75. [PubMed]

4. Busch MP, Satten GA. Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure. Am J Med 1997;102:117-24; discussion 125-6. [PubMed]

5. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173-80. [PubMed]

6. Daar ES, Little S, Pitt J, Santangelo J, Ho P, Harawa N, Kerndt P, Glorgi JV, Bai J, Gaut P, Richman DD, Mandel S, Nichols S; Los Angeles County Primary HIV Infection Recruitment Network. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med 2001;134:25-9. [PubMed]

7. Dear Health Care Professional Letter. “Clarification of risk factors for severe, life-threatening and fatal hepatotoxicity with VIRAMUNE (nevirapine)”, Boehringer Ingelheim, February 2004.  [PubMed]

8. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, Hunt P, Martin JN, Kahn JO, Levy J, McGrath MS, Hecht FM. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004;104:942-947. [PubMed]

9. Delwart E, Magierowska M, Royz M, Foley B, Peddada L, Smith R, Heldebrant C, Conrad A, Busch M. Homogeneous quasispecies in 16 out of 17 individuals during very early HIV-1 primary infection. AIDS 2002;16:189-195. [PubMed]

10. Delwart EL, Sheppard HW, Walker BD, Goudsmit J, Mullins JI. Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays. J.Virol. 1994;68:6672-6683. [PubMed]

11. DHHS guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_032304.html.  Accessed 28 September 2004. [PubMed]

12. Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002;417:95-98.  [PubMed]

13. Farzadegan H, Henrard DR, Kleeberger CA, Schrager L, Kirby AJ, Saah AJ, Rinaldo CR Jr, O'Gorman M, Detels R, Taylor E, Phair JP, Margolick JB. Virologic and serologic markers of rapid progression to AIDS after HIV 1 seroconversion. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13:448-455. [PubMed]

14. Fidler S, Oxenius A, Brady M, Clarke J, Cropley I, Babiker A, Zhang H, Price D, Phillips R, Weber J. Virological and immunological effects of short-course antiretroviral therapy in primary HIV infection. AIDS 2002;16:2049-54. [PubMed]

15. Garcia-Lerma JG, Nidtha S, Blumoff K, Weinstock H, Heneine W. Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons. Proc Natl Acad Sci U S A 2001;98:13907-12. [PubMed]

16. Girard PM, Schneider V, Dehee A, Mariot P, Jacomet C, Delphin N, Damond F, Carcelain G, Autran B, Saimot AG, Nicolas JC, Rozenbaum W. Treatment interruption after one year of triple nucleoside analogue therapy for primary HIV infection. AIDS 2001;15:275-7. [PubMed]

17. Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, Petropoulos CJ, Hellmann NS, Chesney M, Busch MP, Kahn JO. Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 2002;288:181-8.  [PubMed]

18. Gupta P, Mellors J, Kingsley L, Riddler S, Singh MK, Schreiber S, Cronin M, Rinaldo CR. High viral load in semen of human immunodeficiency virus type 1- infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol 1997;71:6271-5. [PubMed]

19. Hecht FM, Busch MP, Rawal B, Webb M, Rosenberg E, Swanson M, Chesney M, Anderson J, Levy J, Kahn JO. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS 2002;16:1119-1129. [PubMed]

20. Hecht FM, Grant RM, Petropoulos CJ, Dillon B, Chesney MA, Tian H, Hellmann NS, Bandrapalli NI, Digilio L, Branson B, Kahn JO. Sexual transmission of an HIV-1 variant resistant to multiple reverse- transcriptase and protease inhibitors. N.Engl.J.Med. 1998;339:307-311. [PubMed]

21. Hecht F, Smith D, Cooper D, Anderson A, Peterson A, Kahn JO. Treatment of primary HIV infection with nelfinavir, zidovudine, and lamuvidine. 1998. Presented at the 12th International AIDS Conference, Chicago, USA, 1998. [PubMed]

22. Henrard DR, Phillips J, Windsor I, Fortenberry D, Korte L, Fang C, Williams AE. Detection of human immunodeficiency virus type 1 p24 antigen and plasma RNA: relevance to indeterminate serologic tests. Transfusion 1994;34:376-80. [PubMed]

23. Hirsch MS, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, D'Aquila RT, Demeter LM, Hammer SM, Johnson VA, Loveday C, Mellors JW, Jacobsen DM, Richman DD. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis 2003;37:113-28. [PubMed]

24. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998;339:33-9. [PubMed]

25. Kassutto S. and Rosenberg ES. Primary HIV type 1 infection. Clinical Infectious Diseases 2004;38:1447-1453. [PubMed]

26. Kinloch-De Loes S, Hirschel BJ, Hoen B, Cooper DA, Tindall B, Carr A, Saurat JH, Clumeck N, Lazzarin A, Mathiesen L. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995;333:408-13. [PubMed]

27. Lacabaratz-Porret C, Urrutia A, Doisne JM, Goujard C, Deveau C, Dalod M, Meyer L, Rouzioux C, Delfraissy J F, Venet A, Sinet M. Impact of antiretroviral therapy and changes in virus load on Human Immunodeficiency Virus-specific T cell responses in primary HIV infection. J Infect Dis 2003;187:748-57. [PubMed]

28. Lafeuillade A, Poggi C, Hittinger G, Counillon E, Emilie D. Predictors of plasma human immunodeficiency virus type 1 RNA control after discontinuation of highly active antiretroviral therapy initiated at acute infection combined with structured treatment interruptions and immune-based therapies. J Infect Dis. 2003;188:1426-32. [PubMed]

29. Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med. 2003;9:861-6.  [PubMed]

30. Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC, Koup RA, Mellors JW, Connick E, Conway B, Kilby M, Wang L, Whitcomb JM, Hellmann NS, Richman DD. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 2002;347:385-94.  [PubMed]

31. Lyles RH, Munoz A, Yamashita TE, Bazmi H, Detels R, Rinaldo CR, Margolick JB, Phair JP, Mellors JW. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis 2000;181:872-880. [PubMed]

32. Markowitz M, Vesanen M, Tenner-Racz K, Cao Y, Binley JM, Talal A, Hurley A, Jin X, Chaudhry MR, Yaman M, Frankel S, Heath-Chiozzi M, Leonard JM, Moore JP, Racz P, Nixon DF, Ho DD, J X. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis 1999;179:527-37. [PubMed]

33. Markowitz M, Jin X, Hurley A, Simon V, Ramratnam B, Louie M, Deschenes GR, Ramanathan M Jr, Barsoum S, Vanderhoeven J, He T, Chung C, Perelson AS, Zhang L, Ho DD. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 2002;186:634-43. [PubMed]

34. Musicco M, Lazzarin A, Nicolosi A, Gasparini M, Costigliola P, Arici C, Saracco A. Antiretroviral treatment of men infected with human immunodeficiency virus type 1 reduces the incidence of heterosexual transmission. Italian Study Group on HIV Heterosexual Transmission. Arch Intern Med 1994;154:1971-6. [PubMed]

35. Mylonakis E, Paliou M, Lally M, Flanigan TP, Rich JD. Laboratory testing for infection with the human immunodeficiency virus: established and novel approaches. Am J Med 2000;109:568-76. [PubMed]

36. Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infections. J Infect Dis 1993;168:1490-501. [PubMed]

37. Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, Sontag G, Sewell AK, Phillips RE. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 2000;97:3382-7. [PubMed]

38. Pilcher CD, Eron JJ Jr, Galvin S, Gay C, Cohen MS. Acute HIV revisited: new opportunities for treatment and prevention. J Clin Invest 2004;113: 937-945.  [PubMed]

39. Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D'Aquila RT, Goulder PJ, Walker BD. Immune control of HIV-1 after early treatment of acute infection. Nature 2000;407:523-6. [PubMed]

40. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996;125:257-64. [PubMed]

41. Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, Farzadegan H, Gupta P, Rinaldo CR, Learn GH, He X, Huang XL, Mullins JI. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol 1999;73:10489-502. [PubMed]

42. Shearer GM, Clerici M. Early T-helper cell defects in HIV infection. AIDS 1991;5:245-53. [PubMed]

43. Simon V, Vanderhoeven J, Hurley A, Ramratnam B, Louie M, Dawson K, Parkin N, Boden D, Markowitz M. Evolving patterns of HIV-1 resistance to antiretroviral agents in newly infected individuals. AIDS 2002;16:1511-9. [PubMed]

44. Soudeyns H, Campi G, Rizzardi GP, Lenge C, Demarest JF, Tambussi G, Lazzarin A, Kaufmann D, Casorati G, Corey L, Pantaleo G. Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor beta chain repertoire and reduces the level of T-cell oligoclonality. Blood 2000;95:1743-51. [PubMed]

45. Vanhems P, Dassa C, Lambert J, Cooper DA, Perrin L, Vizzard J, Hirschel B, Kinloch-de Loes S, Carr A, Allard R. Comprehensive classification of symptoms and signs reported among 218 patients with acute HIV-1 infection. J Acquir Immune Defic Syndr 1999;21:99-106.  [PubMed]

46. Perrin L, Cooper DA, Yerly S. Clinical features of acute HIV-1 infection: zidovudine-resistant isolates compared with zidovudine-sensitive isolates. AIDS 2000;14:1065-7. [PubMed]

47. Vernazza PL, Gilliam BL, Flepp M, Dyer JR, Frank AC, Fiscus SA, Cohen MS, Eron JJ. Effect of antiviral treatment on the shedding of HIV-1 in semen. AIDS 1997;11:1249-54.  [PubMed]

48. Weinstock H, Dale M, Gwinn M, Satten GA, Kothe D, Mei J, Royalty J, Linley L, Fridlund C, Parekh B, Rawal BD, Busch MP, Janssen RS. HIV seroincidence among patients at clinics for sexually transmitted diseases in nine cities in the United States. J Acquir Immune Defic Syndr 2002;29:478-483.  [PubMed]

49. Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, Fischl MA, Gatell JM, Gazzard BG, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Schooley RT, Thompson MA, Vella S, Volberding PA. Treatment for adult HIV infection. 2004 Recommendations of the International AIDS Society-USA Panel. JAMA 2004;292:251-265. [PubMed]

50. Yerly S, Kaiser L, Race E, Bru JP, Clavel F, Perrin L. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet 1999;354:729-33. [PubMed]

51. Yerly S, Rakik A, De Loes SK, Hirschel B, Descamps D, Brun-Vezinet F, Perrin L. Switch to unusual amino acids at codon 215 of the human immunodeficiency virus type 1 reverse transcriptase gene in seroconvertors infected with zidovudine-resistant variants. J Virol 1998;72:3520-3.  [PubMed]

52. Yerly S, Vora S, Rizzardi P, Chave JP, Vernazza PL, Flepp M, Telenti A, Battegay M, Veuthey AL, Bru JP, Rickenbach M, Hirschel B, Perrin L; Swiss HIV Cohort Study. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001;15:2287-92. [PubMed]

53. Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 1993;261:1179-81.  [PubMed]