February 24, 2005
Beyond the hype, this case report raises serious questions regarding the relationship between transmission of drug-resistant virus and rapid HIV disease progression, as well as the adequacy of HIV prevention efforts. These questions were explored in a special session added to the schedule of the annual Conference on Retroviruses and Opportunistic Infections being held in Boston. During the session, the facts of the case were reviewed and examined within the context of our current understanding of transmission, resistance and progression of HIV.
A man in his late 40s developed fever, fatigue and pharyngitis in November 2004. He presented to his physician in December 2004 and a positive HIV antibody test was obtained. At a follow-up medical visit that month his CD4+ cell count was measured as 80 cells/µL and his plasma HIV-RNA level was 280,000 copies/mL.
Previously, from September 2000 to May 2003, this patient had at least 5 HIV antibody tests that were all reportedly negative. The patient also related a history of unprotected anal sex with multiple, sometimes anonymous, male partners, including a series of such encounters over a 2-day period in October 2004. In addition, until November 2004, when he became ill, he frequently abused methamphetamine.
The patient was referred to the Aaron Diamond AIDS Research Center (ADARC) for evaluation of possible recent HIV infection. In January 2005, a detuned HIV enzyme immunoassay was positive -- suggesting the patient was beyond the acute phase of HIV infection. By February 2005, the patient had lost 4 kg and his CD4+ cell count was 28 cells/µL. Several analyses were undertaken, including genotypic and phenotypic resistance testing, characterization of co-receptor usage, flow cytometry of peripheral blood mononuclear cells and mucosal mononuclear cells, viral sequence analysis and host genetic studies.
Resistance testing revealed the patient's virus to be clade B and highly drug resistant. Over a dozen resistance mutations in the reverse transcriptase and protease regions were detected and confirmed. These were associated with significantly reduced susceptibility to 3 of the 4 drug classes used to treat people with HIV: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. However, there was no reduced susceptibility found to enfuvirtide (T-20, Fuzeon), which is the one fusion inhibitor currently approved.
Despite the accumulation of these mutations, the replication capacity of the virus was 136%, indicating this virus was not functionally impaired. Further, the patient was determined to harbor syncytia-forming, dual CCR5 and CXCR4 tropic virus -- findings associated with a more aggressive clinical course of HIV infection. To determine the diversity of the circulating viral population, sequencing of viral DNA from the gag and env regions was conducted and this revealed relatively little variability of the viral population. Interestingly, the patient's virus was unique when compared to viruses banked at ADARC and the Los Alamos National Laboratory.
Compared to HIV-uninfected persons and a small number of patients with early HIV infection, the patient had evidence of profound CD4+ cell depletion in the gastrointestinal tract and blood. CXCR4+ T cells were particularly reduced, suggesting the X4 viral variants were functionally dominant in this patient. Lastly, there was no evidence based on HLA typing and CCR5 genotyping that this patient had a genetic profile associated with altered susceptibility to HIV infection and/or HIV progression rates.
Analysis of the Case Findings in the Context of Previously Described Data on Resistance, Fitness and Progression of HIV
A striking feature of this case is the rapidity with which this patient seemed to have progressed to advanced AIDS. While the phenomenon of rapid progression of HIV is well described, the incidence of accelerated progression to AIDS has not been widely reported.
During this special session, data from 2 large cohort studies of individuals at risk for HIV infection, the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS), and a cohort of recently infected military personnel were reviewed with respect to the variability of the pace of HIV progression following acquisition of the virus.
These studies demonstrate a wide range in the rate of CD4+ cell decline following HIV infection, with rapid progression and long-term non-progression being unusual and most patients falling in between these extremes. Combined data from almost 400 patients in MACS or WIHS who seroconverted during study observation provide estimates that the frequency of progression to AIDS 6 months after HIV infection is 7 in 10,000 patients and in 12 months it is 45 in 10,000 patients. Therefore, rapid progression does occur, albeit rarely. The determinants of rapid progression are still unclear, but data from the military cohort and other studies indicate that host genetic factors may be one of several factors influencing the tempo of HIV progression.
Another notable aspect of the case report is the patient's apparent acquisition of multi-drug-resistant virus. Again, this is not a finding unique to this report as transmission of drug-resistant virus has been previously described. Indeed, in most regions where it has been studied, HIV harboring at least one major resistance mutation now accounts for over 10% of the virus transmitted. However, the accumulation of a large number of mutations across drug classes is exceptional. Notably, the retention of viral fitness in vitro is unusual given the number of mutations present. A theoretical explanation for the preservation of viral fitness of transmitted virus in the face of multiple drug resistance mutations holds that it is only the most functionally fit drug-resistant virus that is likely to be transmitted from one individual to another.
There remain many unanswered questions surrounding this case. Exactly when was the patient infected with HIV? Is the rapidity of his immunologic and clinical decline related to the high-level drug resistance of the patient's virus? Are there host genetic factors that can account for this man's HIV progression? How transmittable is this virus? Did the patient acquire HIV from one individual or from more than a single source over a short period of repeated and intensive exposures? Did the patient's methamphetamine use play any role in his infection and clinical course? Importantly, for this man, how can this infection best be treated?
Further, given the obvious public health implications of the report, what responses should follow? Foremost, is the concern that aggressive and/or multi-drug-resistant HIV is being transmitted -- perhaps in a network of men who have sex with men. Although this is a serious and valid fear, the transmission of any type of HIV is concerning.
Dr. Harold Jaffe, formerly of the U.S. Centers for Disease Control and Prevention, offered a measured perspective on the public health options available in response to this case report. This included efforts to elucidate the sexual network(s) the patient was involved with, and investigation and outreach at venues where this man met new sexual partners.
In addition, Dr. Jaffe proposed the development of a system encouraging clinician reporting of multi-drug resistance in antiretroviral-naive patients as well as a surveillance to detect HIV outbreaks. However, he warned of the double-edged nature of the application of scare tactics as a prevention method. While the attention this case has received may raise the consciousness and safe-sex conscientiousness of individuals at risk for HIV infection, fear can also provoke a backlash leading to the (further) stigmatization of groups perceived to be at risk of acquiring and transmitting HIV.
Indeed, the publicizing of this case prior to this conference has been criticized by many AIDS advocacy organizations as being insensitive to the potential for the report to lead to demonization of gay men. Dr. David Ho, of the ADARC, who presented the details of the case report, defended the actions of his team who, soon after evaluating the patient, alerted public health officials in New York City of the potential that a highly resistant and pathogenic virus was circulating.
Lastly, the case has renewed calls for significant improvements in HIV prevention efforts and substance abuse treatment. Several indicators suggest that methamphetamine abuse is promoting increased uptake of HIV transmission risk behaviors, fueling the spread of HIV in certain areas. Yet, access to quality substance abuse treatment is uneven.
Beyond the publicity and the political posturing, this report of a single unusual case raises important scientific questions that require further intensive study. Certainly, the coming weeks will see the report of additional information regarding this patient and his virus.
The case report also makes more widely known that a) HIV is still being transmitted, b) there exists a real risk of acquiring HIV that is resistant to HIV therapies and c) it is completely misguided the notion among some uninfected individuals that infection with HIV can be risked since HIV infection can be easily medically managed as a chronic disease.
Similarly, the case dramatically highlights the shortcomings of our initiatives to control the spread of HIV in the United States. Rates of new HIV infection have changed little over the past several years and an increase in HIV acquisition among young men who have sex with men suggests prevention efforts are falling short of reaching those most at risk.
This report details an unfortunate and sad event. Hopefully, the lessons learned will provide guidance in our efforts to prevent this case report from becoming a case series.