Why HIV Virus Infection Rates Are on the Rise
"Men Who Have Sex With Men, Risk Behavior, and HIV Infection: Integrative Analysis of Clinical, Epidemiological, and Laboratory Databases"
(see CID publication below)|
"Our finding of an increasing number of recent infections, syphilis comorbidity, expanding range of subtypes, HIV drug resistance spread, and phylogenetic clustering of multiple infections indicates that unprotected sex has become more common among MSM in Israel and that this is not entirely a problem of insufficient awareness of the risks, as suggested also in some behavioral surveys in different countries. Action by public health planners and community-based organizations to further increase awareness of the risks and to establish community norms of safe sex practices are called for."
www.therapeuticsdaily.com, From the PharmaLive.com News Archive - Aug. 25, 2011
TAU researcher finds already-medicated patients are passing on the virus
TEL AVIV, Aug. 25, 2011--Since HIV infection rates began to rise again around 2000, researchers have been grasping for answers on what could be causing this change, especially in the homosexual community. The rising numbers are a stark contrast to the 1990's, when infection rates dropped due to increased awareness of the virus. A new study in Israel reveals that the number of new HIV cases diagnosed each year in the last decade saw a startling increase of almost 500% compared to the previous decade, and similar trends have been reported in a number of other developed nations, including the U.S.
According to Prof. Zehava Grossman of Tel Aviv University's School of Public Health at the Sackler Faculty of Medicine and the Central Virology Laboratory of the Ministry of Health, a new approach to studying HIV transmission within a community has yielded a disturbing result. By cross-referencing several databases and performing a molecular analysis of the virus found in patients, an astonishingly high number of newly-diagnosed men with male sexual partners were found to have contracted the virus from infected, medicated partners who are already aware of their HIV-positive status.
Reported in the journal Clinical Infectious Diseases, these findings indicate that the public health approach towards HIV counselling and education needs to be reconsidered, Prof. Grossman says.
Bypassing the questionnaires
Prof. Zehava Grossman
Researchers had begun to suspect that the rise in infection rates was due to a change in social behavior, but hard evidence was lacking. The answers, Prof. Grossman says, were not easy to find by asking the patients themselves.
Questionnaires and similar methods to gather information are hard to interpret because, in addition to the difficulty of recruiting an accurate cross-section of the population, people are often unwilling to be frank about risky sexual behavior.
To unravel the mystery, Prof. Grossman and her colleagues at the Central Virology Laboratory directed by Prof. Ella Mendelson and Israel's leading AIDS clinicians turned to the virus itself. Working with senior epidemiologists of the Public Health Services of Israel's Ministry of Health, they conducted a comprehensive analysis of laboratory, clinical, and epidemiological data, including information about patients' diagnosis and treatment, sexually transmitted diseases contracted along with HIV, and the molecular characteristics of the virus in different patients.
Prof. Grossman and her colleagues found that an overwhelming number of new cases were infected with HIV strains that had already developed resistance to existing HIV drug therapies. Because the virus can only become resistant if previously exposed to medication, this result indicates that new patients are often infected by an HIV-positive partner already receiving the therapies. More often than in the past, HIV found in different patients could be traced back to a common source.
Changing the educational approach
While people are now more knowledgeable about the virus and aware of the risks of unprotected sex, it appears that an increasing number of homosexual men, including those who are infected and treated for HIV, are likely to engage in risky sexual behaviour. Public health authorities, educators, and activists should be encouraged to find new ways of changing this attitude and of better imprinting the message about the risk and consequences of HIV transmission, particularly within the gay community.
Clearly, Prof. Grossman warns, the need to establish the values of safe sex within at-risk populations is as imperative as it has ever been.
Men Who Have Sex With Men, Risk Behavior, and HIV Infection: Integrative Analysis of Clinical, Epidemiological, and Laboratory Databases
(See the editorial commentary by Mayer and Mimiaga, NATAP email
Background. Centralized data collection and analytic tools facilitate tracing HIV transmission trends at the patient-population level with increasing resolution, complementing behavioral studies while avoiding sampling biases. By several measures, the rate of HIV infection among men who have sex with men (MSM) in Israel increased in the past several years more rapidly than was expected. We describe features of the data that connect this increase to behavioral changes.
Methods. We retrospectively analyzed data from the national HIV reference laboratory and the national HIV and sexually transmitted infections registries. We examined changes in selected epidemiologic and clinical parameters and in the pattern of drug-resistant virus transmission among MSM in Israel. In particular, virus isolates from 296 MSM (23.8% of all MSM who received a diagnosis) were genotyped, drug-resistance conferring mutations were characterized, and phylogenetic trees were constructed.
Results. Compared with earlier years, during 2007-2009 MSM were more often infected with drug-resistant virus before treatment initiation, were coinfected with syphilis, and received a diagnosis during acute retroviral syndrome. Phylogenetic analysis suggested frequent transmission of drug-resistant HIV by drug-treated individuals to >1 partner. Secondary transmission of resistant virus by drug-naive patients is also consistent with the phylogenetic patterns. In addition, non-B HIV subtypes began to appear among MSM.
Conclusions. Together, our findings suggest that the sexual behavior of MSM, both HIV-infected and uninfected, has become riskier, contributing to the number of those seeking early clarification of status, to syphilis comorbidity, and to the spread of drug resistance. These findings call for action by public health planners and community-based organizations aimed at increasing awareness of the risks, bringing a change in attitude and establishing safe sex norms.
In recent years, the majority of men with newly diagnosed HIV infection in Israel were MSM. Infected MSM were typically Caucasian Jews (median age ± SD, 33 ± 10 years) who contracted the virus in Israel or in other industrial countries . Until recently, all MSM had subtype B, but recently, MSM carrying A/AE and C viruses were identified. The greater variety suggests risky sexual behavior with larger groups of sex partners.
In addition to these trends, higher rates of syphilis were detected among HIV-infected MSM, as reported also in other countries [20, 21], indicating an increasing tendency of practicing unsafe sex in this group. Syphilis may increase viral load, thus facilitating further spread of virus and exacerbating the consequences of irresponsible conduct [22, 23]. HIV infection, in turn, might facilitate the spread of the spirochete  in a vicious cycle. Although, in Israel, there is general awareness of the risks, it appears that the success of HAART and other factors have diminished concerns regarding the risk and consequences of HIV transmission, resulting in behavioral disinhibition among MSM .
Frequent engagement in risky behavior was also reflected by the spread of drug-resistant virus. The increasing number of patients with newly diagnosed HIV infection who were carrying resistance-conferring mutations indicates that treated patients increasingly practice unprotected sex. Indeed, the same mutations prevalent in the treated population are now also those most prevalent in the drug-naive population (with the exception of M184V, which affects the active site of the reverse-transcriptase enzyme and, therefore, disappears rapidly when the selection pressure of the drug is removed ). Responsibility for the risky behavior underlying the observed trends may be ascribed, perhaps to a different degree, to both uninfected and infected partners; certainly, the drug-treated partner is aware of his HIV status. The higher percentage of MSM who received a diagnosis relatively soon after being infected and even before seroconversion suggest also that many MSM may be aware of having practiced risky sexual contact and/or are sensitive to initial signs of infection. Although such awareness did not prevent their initial risky behavior, they appear to seek immediate clarification of their infection status and medical advice. Collection of relevant behavioral data is required to assess the validity of this conjecture. In any case, the data are consistent with a higher degree of risk awareness rather than the opposite. Detection of HIV positivity at an earlier stage after infection, as observed, should tend to diminish the rate of virus transmission among MSM, but evidently, this was not enough to reverse the present trends.
Our phylogenetic analysis provided further insights that corroborate the aforementioned inferences regarding the trend of increased risky behavior among MSM. This analysis revealed a considerable increase after 2007 in the proportion of MSM infected with closely related viruses. In particular, several clustered viruses share a common resistant-conferring mutation, and most drug-resistant viruses reside in clusters. Such clustering suggests either a common source of virus (drug-treated patient) or secondary transmission among drug-naive carriers of the virus in a relatively short time, as was suggested in other studies [13, 27]. We cannot distinguish between the 2 possibilities, because such distinction would require analyzing larger numbers of treated and untreated HIV-infected MSM and/or a detailed epidemiological investigation. However, because the observed clusters represent a significant proportion of all those MSM infected with drug-resistant virus and because finding the mode of transmission of the same drug-resistant virus to men could be particularly instructive, additional studies would be of interest. In clusters, there was an increased representation of syphilis coinfection, consistent both with the association of syphilis with unsafe sex and with the potential synergy between syphilis and HIV infection.
Beyond the concrete findings that we have reported, this work and the work of others reveals that centralized databases and modern analytic tools allow the tracing of virus transmission trends, at the patient population level, with increasing resolution, potentially complementing behavioral studies while avoiding some of the sampling biases of those . The major limitation of the present study is that the number of MSM infected with drug-resistant virus in Israel is still relatively small. Moreover, our analysis did not incorporate all the data gathered in Israel on this subpopulation of MSM infected with drug-resistant HIV, because data from 1 major AIDS center (of seven) was not available to us.
Our finding of an increasing number of recent infections, syphilis comorbidity, expanding range of subtypes, HIV drug resistance spread, and phylogenetic clustering of multiple infections indicates that unprotected sex has become more common among MSM in Israel and that this is not entirely a problem of insufficient awareness of the risks, as suggested also in some behavioral surveys in different countries. Action by public health planners and community-based organizations to further increase awareness of the risks and to establish community norms of safe sex practices are called for.
Data regarding the frequency and distribution of HIV infection in populations at risk are important in monitoring and controlling the epidemic. Incidence rates of HIV infection are influenced by several factors, including the sizes of the infected populations, migration, availability of highly active antiretroviral therapy (HAART), and various behavioral activities .
By the end of 2009, 3800 male adults infected with HIV-1 were reported in Israel, of whom 1243 (32.7%) were men who have sex with men (MSM). Until 1991, HIV-infected MSM were the group with the greatest number of reported cases in the country [1-3] (Figure 1A). During the early 1990s, MSM adopted risk-reducing strategies, and at the same time, there was a large wave of immigrants from Ethiopia, among whom prevalence of HIV infection is high, reducing the absolute number of new cases per year among MSM and the proportion of MSM in the population of HIV-infected persons [3, 4]. These trends were reversed during the later 1990s, and during the past decade, the annual number of MSM with a new diagnosis of HIV infection in Israel has increased by 4-5-fold (Figure 1B). This phenomenon requires an explanation, while the (more modest) increases in annual numbers of newly diagnosed cases in members of other transmission groups in the same period, especially injection drug users, can be readily accounted for by changes in the immigration to Israel from the former Soviet Union and East Africa.
Part of the increase in the incidence rate of HIV infection during 2002-2009 in Israel could be accounted for by the growth in the overall population of infected MSM during that period. Thus, we would have expected the number of new transmissions among MSM in 2009 to have increased in proportion to the growth in the total number of infected MSM even if the mean probability of an infected individual of infecting other men in 2009 remained the same as that in 2002. This is the case because, in the meantime, the collective source of virus expanded and the number of uninfected MSM is not limiting. In fact, it can be estimated roughly that the total number of HIV carriers among MSM in Israel less than doubled during the considered period, which leaves more than half of the 4.3-fold difference in the number of MSM with newly diagnosed HIV infection during 2002-2009 (Figure 1B) unaccounted for.
Developing solid understanding of the dynamics of HIV infection trends requires collecting and rigorously analyzing a large body of data, and the best way of doing it is in a centralized manner . A national HIV registry and a National HIV Reference Laboratory (NHRL) were established in Israel in 1986. All physicians and laboratories are required to report every newly diagnosed case to the national registry, reporting patient identification details, sex, year and country of birth, year of arrival in Israel, and mode of HIV transmission. In addition, all the peripheral laboratories send their positive enzyme-linked immunosorbent assay results to the NHRL, which performs the confirmatory Western blot assay and reports to the national registry. Thus, the registry is both accurate and sensitive to changes in the overall trends of the epidemic. The NHRL also performs the majority of drug resistance analyses, facilitating integrative studies.
Assessing behavioral changes usually relies on the direct collection of behavioral data from the target population. This approach is not always feasible, and performing appropriate probability sampling in a population such as MSM is inherently difficult . It is desirable to combine information based on directly investigating the behavior of persons with the results of studies that rely primarily on laboratory data, including in particular, evolution of the virus in the population.
The purpose of the present study was to assess the possible role of behavioral changes in accelerating the spread of HIV infection among MSM in Israel over time through a detailed examination of the shifting patterns of drug-resistant virus transmission in this group and of other parameters, including presentation with syphilis at the time of diagnosis of HIV infection and the frequency of cases in which HIV positivity is detected relatively soon after infection. Drug-resistant virus transmission is a marker of unsafe sex practiced by actively treated patients and their sex partners. The frequency at which new cases are diagnosed soon after the infection occurred may indicate to what degree sexually active MSM are collaborating with efforts by doctors and public health officials to minimize the time between infection and its detection, for the patient's benefit but also to reduce the risk of secondary infections during the time after infection when such risk is particularly high. Early diagnosis might also reflect awareness by patients who received a diagnosis of having practiced unsafe sex. In any case, a trend toward earlier diagnosis can be considered to be indirect evidence that the increasing rates of infection among MSM are not attributable to a widespread ignorance regarding the risks of unsafe sex (although they might be attributable to ignoring those risks). Coinfection with syphilis can be regarded as a surrogate marker for unsafe sexual practices. Indeed, syphilis is the most infectious of all sexually transmitted diseases.
Increase in incidence of HIV infection among MSM was also noted during the early 2000s in the United States  and several European [8, 9] and African  countries. It was related to behavioral changes, especially an increase in unprotected anal intercourse . Although our study was limited to a relatively small MSM population in a small country, the issues considered, the methods implemented, and the lessons from this study are pertinent to many other communities of broadly similar characteristics .
We identified cases of recent HIV infection at diagnosis retrospectively either by documented evidence that seroconversion occurred in the preceding 12 months or when acute retroviral syndrome was documented, based on a compatible pattern of viral load, CD4 cell count, and clinical history [13, 14].
Infectious syphilis (primary, secondary, or early latent) was defined by a Venereal Disease Research Laboratory (Becton-Dickenson) titer >1:8 in a patient with positive Treponema Pallidum Haemagglutination (Axis Shield) and/or positive Fluorescent Treponemal Antibody) (BioMrieux) results, with a compatible clinical history. Because syphilis is a notifiable disease, data from the national sexually transmitted diseases registry at the Ministry of Health was cross-checked with the national HIV registry data. Data on syphilis prevalence in the entire MSM population was not available to us.
Viruses from a total of 884 male patients (23.3% of all identified in Israel until the end of 2009) were genotyped at the NHRL before initiation of treatment. These patients include 3 groups that together are representative of resistance among drug-naive patients. First, from 2002 through 2006, isolates from a group of persons with newly diagnosed cases were genotyped as part of the international SPREAD program, carefully selected to be representative of drug-naive HIV-infected persons in the participating countries [15-17]. Second, since 2007, isolates from all persons with newly diagnosed cases are genotyped as part of clinical evaluation; >80% of isolates are genotyped at NHRL. Isolates from only 94 drug-naive patients (11 MSM and 83 others) who received a diagnosis before 2002 were genotyped without particular selection.
We retrospectively analyzed all the available molecular data, focusing on the 296 MSM found among the 884 infected male patients. These MSM included 165 drug-naive and 148 drug-treated patients from 6 of the 7 AIDS centers in the country (for 17 individuals, we had samples obtained both before and after treatment initiation). Genotyping was performed using the HIV-I Truegene kit (Siemens). Only the first available sequence from each patient was included. Resistance-conferring mutations were defined according to the criteria suggested by Bennett et al . For comparisons of mutation frequencies among MSM and other patients, we used the χ2 test for the categorical independent variables or Student's t test for the continuous independent variables; P values <.05 were considered to be statistically significant. Analyses were conducted using SPSS, version 14.0, for Windows.
Phylogenetic and molecular evolutionary analyses of 270 sequences from 165 drug-naive and 105 drug-treated patients were conducted using MEGA, version 4  and the ClusalX method (MegAlign, Lasergene, version 5.01, DNAStar). Phylogenetic trees were drawn using FigTree, version 1.3.1, and branch reproducibility was performed on 1000 replicates using Seqboot. Subtyping was based on the Stanford Rapid Subtyping tool (www.hivdb.stanford.edu/hiv/).
The study was approved by the Ethical Committee of the Sheba Medical Center.
Number and Proportion of MSM Newly Diagnosed With HIV
By the end of 2009, 6250 persons infected with HIV-1, including 3800 men >15 years of age, were reported in Israel (Figure 1A). They consisted of MSM (32.7%), immigrants from Ethiopia (32.3%) and from other areas of endemicity (mainly Sudan and Eritrea, 15.4%), and injection drug users (17.9%) (Figure 1A). Of the latter, 61% emigrated from the former Soviet Union (mainly, Ukraine and Russia). The proportion of MSM among all persons with newly diagnosed HIV infection was 38% during the late 1980s, decreased to 7% during the 1990s, and has been increasing constantly since 2000, reaching 35% in 2009 (Figure 1B).
Most of the infected MSM (68.9%) were born in Israel and 6.9% in the former Soviet Union, mainly Ukraine. Fifty-two percent were infected in Israel and 7% in the United States or Western Europe; for 41%, place of infection was not known. The implication of this and the fact that most infected MSM carry subtype B viruses is that the MSM epidemic in Israel is essentially homegrown and that factors, such as tourism and immigration, do not significantly confound the results.
Recent Infection With HIV-1 Among MSM With Newly Diagnosed HIV Infection
Until the end of 2009, 237 individuals were recently infected at the time of diagnosis (as defined in Methods). Eighty-six of these were MSM (7.9% of all MSM who received a diagnosis)-a proportion significantly higher than in the other known risk groups (P < .001). A significant increase in the proportion of MSM with newly diagnosed cases who were recently infected, many of them before or during seroconversion, was seen in recent years. Whereas during 1986-2006, only 4% of MSM who received a diagnosis had been recently infected; during 2007-2009, the proportion increased to 14% (P = .02). Data extracted from the AIDS clinic at the Sheba Medical Center (1 of 7 centers in the country, serving the Tel-Aviv metropolitan area) demonstrated an increase that was even greater: during 1986-2006, only 4 (2%) of 198 MSM who received a diagnosis at this clinic were recently infected, and during 2007-2009, 32 (28%) of 116 MSM with newly diagnosed cases were recently infected (P < .0001).
MSM Coinfected With HIV and Syphilis
Cross-checking data from the national sexually transmitted diseases registry and the national HIV registry showed a trend of increase in syphilis incidence rates among HIV-infected MSM similar to the increase in incidence rates of HIV infection during most of the 2000s, with some limited decrease in 2009 (Figure 2).
Drug Resistance Among Patients With Newly Diagnosed HIV Infection
Isolates from 884 male patients (23.3% of all identified in Israel until the end of 2009) were genotyped at the NHRL before treatment initiation. Drug resistance among isolates from patients with newly diagnosed cases was high during the 1990s (20%), decreased during the early 2000s (8%) , and increased until the end of the study period. Among the different risk groups, drug-resistant viruses were most frequently found in MSM. During 2007-2009, ~29% of all MSM with newly diagnosed cases carried HIV bearing at least 1 major resistance-conferring mutation, while only 7% of all other patients who received a diagnosis during this period had such mutations (Table 1 and Figure 3; P = .015).
The most common drug resistance mutations in samples from drug-naive patients occurred in reverse transcription amino acids 103 (6%) and 215 (4%) and in Pr amino-acid 90 (2%), reflecting the common pattern of resistance development in patients experiencing failure of drug-combination treatment. Transmission of drug-resistant virus to drug-naive patients was more common during 2007-2009 (Table 2, Figure 4).
Phylogenetic Analysis of Viral Protease and Reverse Transcriptase From Infected MSM
Phylogenetic trees of Pr-RT sequences from 270 patients (165 drug-naive and 105 treated) were constructed. We divided the sequences into early (1986-2006; 145 patients) (Figure 4A) and late (2007-2009) (125 patients) (Figure 4B), according to time of diagnosis. This enabled us to better envision and characterize trends of change (Table 3).
During the first years of the epidemic, all MSM in Israel were infected with HIV subtype B. Other subtypes have been identified in this transmission group only since the beginning of this century; in 2001, the first (of 17) A/AE case and, in 2003, the first (of 8) subtype C case were identified. Establishment of A/AE infection among MSM is particularly evident since 2007 (Figure 4).
Drug-resistant virus of all subtypes was found in the population of drug-naive patients (Table 1).
The phylogenetic trees show frequent transmission of drug-resistant viruses during the last 3 years of the study. In addition to resistance transmission from treated patients to uninfected individuals, drug-resistant virus might have also been transmitted to such individuals by other drug-naive carriers of the virus. Thus, the drug-naive individuals infected with closely related viruses bearing the protease mutation L90M (4 cases) or the reverse transcriptase mutations K103N (6) or T215Y (3 and 2) (Figure 4B) might, in each case, have been infected by a single patient receiving HAART or, alternatively, infected each other in a relatively short period (the original drug-treated patients are unknown). This would mean that transmission of resistant virus by drug-naive carriers of such virus could have involved up to 65% of all transmissions (15 of 23 infection events) in the studied group. Other clusters showing sequence similarity but not shared resistance mutations also suggest the same phenomenon of virus being increasingly transmitted by single individuals to several uninfected partners and/or chain transmission. Overall, clustering was more common in the late group than in the pre-2007 group (Figure 4).
Figure 4B shows that syphilis was in correlation with clustering. Of the 16 MSM with newly diagnosed HIV infection who were found to be coinfected with syphilis during 2007-2009, 11 (69%) were found in multiples in clusters of closely related viruses. Although the numbers are modest, the probability that the observed distribution resulted from random associations is small.