HIV Eradication: A Status Report From the 17th International AIDS Conference

The 17th International AIDS Conference was held this year from August 3 to 8 in Mexico City. Almost 25,000 people from 200 countries attended.

This month's Managing Managed Care reviews just a few of the many presentations from the International AIDS Conference that have some relevance to patient care today. One of the highlights was a discussion of the current status of HIV eradication. While we are not there yet, there is encouraging news for patients. Other topics discussed here include patient retention in care, hepatitis coinfections, and the continuing discussion of safer sex for men who have sex with men (MSM).

HIV ERADICATION: STILL ON THE AGENDA
Siliciano¹ (Johns Hopkins University) presented a thought-provoking and understandable status report on HIV eradication. According to Siliciano, there are 3 important goals that need to be met in order to eradicate HIV from persons who are HIV-infected (Table).

1. Suppress replicating virus.
2. Identify all of the stable reservoirs where nonreplicating forms of the virus persist in the body.
3. Identify ways we can eliminate each of those reservoirs.

He said that everyone who is receiving potent antiretroviral therapy and has an undetectable viral load is viremic to some degree. Using highly sensitive assays, it is possible to detect "residual viremia," which represents free virus particles in the blood of patients with undetectable viral loads. His explanation is that residual viremia represents release of virus from stable reservoirs (ie, cells that were infected before the start of therapy). In other words, according to his hypothesis, antiretrovirals actually stop viral replication. The good news is that this free virus is the same virus or is very similar to virus harbored in stable reservoirs.

He did not recommend adding a fourth antiretroviral drug to a potent regimen because this free virus has no ongoing cycles of replication.

Siliciano's conclusion is that we have accomplished goal number 1 above, ie, suppression of replicating virus with antiretroviral therapy.

With an understanding of what free virus represents, Siliciano then discussed the viral reservoir issue in more detail and described a reservoir other than latent HIV in resting CD4⁺ cells. His current hypothesis is that in some patients, HIV is also harbored in a stem or other progenitor cell that is able to divide after infection (eg, monocyte/macrophage line). Overcoming goal number 2 will require further study to support this hypothesis, since knowing where the virus is sequestered is essential to successful eradication.

The third goal, the eradication of the known reservoirs, is still very much a laboratory exercise. Theoretically, activating resting CD4⁺ cells to liberate and treat latent virus is problematic at this point. Agents that induce global T-cell activation also turn on latent HIV. Unfortunately, these agents also activate all of the uninfected resting CD4⁺ cells that go on to produce cytokines in such large amounts that this results in unacceptable toxicity to the patient. The next step in the process is to find agents that can turn on latent HIV without inducing global T-cell activation.

Siliciano closed his discussion on an encouraging note. The fact that current antiretroviral drug regimens can stop ongoing viral replication is really of enormous significance because it takes away HIV's main weapon: the ability to evolve. He believes that this means "treatment failure is not inevitable." Even with the drugs we have today, or with agents similar to today's, if we can develop drugs that could be taken for life without unacceptable toxicity, then "it is, in principle, possible to offer everyone who is currently living with HIV infection the chance for a normal life."

RETENTION IN CARE: TRACK IT AND DEAL WITH IT
According to a study by Gerver and colleagues,² of 2071 patients registered at a London clinic, 801 (38.7%) had not been seen for more than 12 months. Of these, 421 (52.6%) had not received care elsewhere and were defined as lost to follow-up, although 20.7% had been receiving antiretroviral therapy and 17.3% had a CD4⁺ cell count under 200/µL at their last visit.

Independent risk factors associated with being lost to follow-up were being a black heterosexual male (odds ratio [OR], 6.00 vs white MSM; P < .001), being female (OR, 4.04 vs white MSM; P < .001), or having attended the London clinic for less than 3 months (OR, 1.65 vs 1 year or longer; P = .01). In a chart review to determine the possible reasons for lost to follow-up, a subset of the lost to follow-up patients (27.2%) reported plans to leave the United Kingdom. Ten percent of patients in this group had not been seen after initial diagnosis, and 3% were reported to be in denial of their status.

The authors highlighted the need to better understand the health-seeking behaviors of patients accessing HIV care and suggested some changes to clinic procedures in order to limit the number of patients lost to follow-up:
• Regular updating of contact information by clinic staff.
• More frequent tracking of patients who appear to be lost to follow-up.
• Formally recording transfers of patients to other clinics.
• More intensive monitoring and support of patients in their first 6 months at the clinic, including more counseling, peer support, and linkage to other services.

HEPATITIS COINFECTIONHepatitis B
Occult hepatitis B virus (HBV) infection was strongly linked to HIV-related immune suppression in a cohort of US women, but occult hepatitis C virus (HCV) infection was rare, according to another presentation at the Conference.³ Occult infection refers to persistent HBV or HCV infection without typically detectable serological markers (antigens or antibodies in the blood) in persons who test positive for viral genetic material (HBV DNA or HCV RNA). Because of differences in definitions and testing methods, various studies have estimated the prevalence of occult HBV infection at 0% to 89%, and the prevalence of occult HCV infection at 0% to 13%.

Taylor and colleagues³ (Brown University) conducted a retrospective analysis of data collected between 1993 and 2000 from 549 HIV-positive and 296 at-risk HIV-negative women in the HIV Epidemiology Research Study (HERS) cohort. Occult HBV infection was defined as persistent HBV DNA in the blood without detectable hepatitis B surface antigen (HBsAg), while occult HCV infection was defined as detectable HCV RNA with undetectable antibodies against the virus at 2 time points 6 months apart.

At the baseline study visit, the researchers screened the women for HBsAg (detectable in 2.6%), hepatitis B core antibodies (positive in 52%), and HCV antibodies (positive in 54%). At the second time point, they mea­sured HBV DNA and HCV RNA levels (using ultrasensitive Roche COBAS TaqMan nucleic acid assay), with a limit of detection of 15 IU/mL for HBV and of 11 IU/mL for HCV. At the third time point, they again measured both serological markers and HBV DNA and HCV RNA levels.

Among the women initially classified as having occult HBV infection, some had disease that progressed to chronic infection, suggesting that their infection was in the acute stage when they were tested at the earlier clinic visit; some spontaneously cleared the virus, leaving 26 (3.2%) with persistent occult HBV infection by the final visit. Looking only at the HIV-positive women, however, the rate of persistent occult HBV infection was 4.7%.

All of the women with occult HBV infection were HIV-positive, compared with 79% of those with chronic HBV infection and 69% who were exposed to the virus but had cleared it. Women with occult HBV infection were significantly more likely than chronically infected women to have a history of injection drug use (88% vs 57%) and to also be infected with HCV (88% vs 43% for HCV antibodies; 77% vs 29% for HCV RNA).

In an analysis of only the women who were HIV-positive, those with occult HBV infection had a lower CD4⁺ cell count (205 vs 326/µL) and a higher HIV RNA level (36,725 vs 4480 copies/mL) than those who had evidence of HBV exposure but had cleared the virus. Women with occult HBV infection were also more likely to currently inject drugs (54% vs 32%) and to drink alcohol heavily (23% vs 9%). None of the women whose antiretroviral regimen included lamivudine, which is active against HBV as well as HIV, had detectable HBV DNA.

Occult hepatitis C was found to be much less common than occult hepatitis B. Of the 33 women initially classified as having occult HCV infection, chronic infection developed in 24; 8 had cleared the virus; and only 1 had persistent occult HCV infection.

The researchers concluded that occult HBV infection is associated with HIV infection and may be a particular problem for women who do not achieve an undetectable viral load. While chronic HCV infection was common in this cohort, occult HCV infection occurred rarely.

Hepatitis C in MSM
Although HCV is rarely transmitted sexually, since 2000, outbreaks of sexually transmitted HCV infections among HIV-infected MSM have been reported. A study from the Netherlands presented by Urbanus and colleagues4 looked at the HCV prevalence and risk factors among MSM at a large sexually transmitted infection (STI) clinic, which reports 24,000 new consultations each year.

In May and November 2007, 2061 attendees of an Amsterdam STI clinic were interviewed about risk factors for blood-borne and sexually transmitted infections and anonymously screened for HIV and HCV antibodies. Additional HCV RNA tests were performed in all HIV- infected participants regardless of their HCV antibody status. Determinants of HCV infection were analyzed using logistic regression. Genetic sequencing using the phylogenetic analysis method was done to determine evidence for sexual transmission.

In total, 448 of the 2061 STI clinic patients were MSM. Two of the 358 (0.6%) HIV-negative MSM and 14 of the 90 (15.5%) HIV-positive MSM were coinfected with HCV, with 1 of the 2 HIV-negative and 3 of the 14 HIV-positive MSM ever having injected drugs. Three of the 14 HIV/ HCV-coinfected MSM tested negative for HCV anti­bodies but had detectable HCV RNA levels, which may be indicating acute infection. In a multivariate analysis, HIV infection (OR, 14.31; 95% confidence interval [CI], 1.09 - 187.9), "fisting" (OR, 57.4; 95% CI, 4.01 - 820.67), and injection drug use (OR, 18.07; 95% CI, 1.05 - 309.9) were significantly associated with HCV infection. Fisting in itself was strongly correlated with the use of sex toys, group sex, bleeding during sex, and use of the recreational club drug g-hydroxybutyrate (GHB). Phylogenetic analyses including previously known cases of acute HCV infection in MSM revealed a high degree of MSM-specific clustering or similarity among the viral strains.

These investigators found an HCV coinfection prevalence of 15% in HIV-infected MSM who attend the STI clinic, whereas before 2000, the prevalence rate ranged from 1% to 4%. The increasing prevalence of hepatitis C and the possibly acute infections suggest a rapid spread of hepatitis C. Also, rough sexual techniques were independently associated with HCV infection. Phylogenetic analysis revealed the presence of MSM-specific HCV strains, also supporting sexual transmission. Targeted interventions, including raising awareness, are needed to stop the further spread among HIV-infected MSM and the potential spillover to HIV-negative MSM.

ERECTILE DYSFUNCTION ATTRIBUTED TO CONDOM USE
If gay men experience erection loss when they use condoms for insertive anal sex, they are less likely to use condoms over the following 6 months and less likely to intend to use condoms again, according to the findings from another Dutch study reported by Lammer and associates.⁵ So-called COINED (COndom INduced Erectile Dysfunction) was such a strong independent predictor of subsequent premeditated (as opposed to unpremeditated) unprotected sex, these Dutch researchers found, that condom-related erectile dysfunction could be used as a surrogate marker for unprotected sex. Because erection loss influenced future sexual behavior, the researchers concluded that the messages regarding condom use in MSM should be reexamined.

The researchers looked at the relationship between COINED and deliberately risky sexual behavior in 435 men, 6% of them HIV-positive, who took part in the Am­sterdam Cohort Studies of Homosexual Men. COINED was self-defined as "prematurely losing erection when using condoms" and was measured by a 5-point scale (1 = never to 5 = always), and was corrected for other types of erectile dysfunction.

The men (mean age, 34 years) were asked to complete questionnaires detailing self-reported COINED, deliberate and nondeliberate risky unprotected insertive anal intercourse (UIAI) with casual and steady partners, and their intentions to use condoms. Deliberate risk was defined as UIAI that was planned in advance, while COINED was defined as loss of erection because of condom use. The data from the questionnaires suggested rates of UIAI reached 18% (55 of 306) with casual partners and 17% (46 of 272) with steady partners of discordant or unknown HIV status. Ten percent frequently experienced COINED with casual partners and 7% with steady partners.

Further analysis suggested that COINED was not associated with UIAI with steady partners. But among casual partners, COINED was significantly associated with deliberate UIAI (OR, 6.57) but not with non-deliberate UIAI. The researchers conclude that COINED is a unique predictor of deliberate UIAI between casual partners.

If men experienced COINED, they were 2.71 times more likely within 6 months to have risky UIAI (P = .05) with casual partners and 2.57 times more likely with steady partners (not statistically significant). With steady partners, men with COINED tended to avoid anal intercourse, being 3 times less likely to have it (not statistically significant). Men who had experienced COINED were 63% more likely to have UIAI over the next 6 months and 59% more likely to intend not to use condoms over the next 6 months, which suggests that COINED could be a surrogate measure or predictor of deliberately unprotected sex. HIV status had no relation either to COINED or to deliberately planned unprotected sex.

While the researchers did not look at recreational drug use, they wanted the survey questions designed to look specifically for erection loss with condom use and not for gathering information on drug use.

Since COINED influences the intention to use condoms, traditional "intention-based" prevention strategies will probably be ineffective in addressing this problem. According to the researchers, alternative strategies, such as the use prescription drugs for erectile dysfunction, should be considered. At a minimum, we as health care providers should be asking our patients about their ability to maintain an erection when using condoms when we talk with them about safer sex.

References:

References

1.

Siliciano R. HIV persistence on patients on HAART: re-evaluating prospects for eradication. 17th International AIDS Conference; August 5-8, 2008; Mexico City. Abstract TUAB0205.

http://www.kaisernetwork.org/health_cast/hcast_index.cfm?display=detail& hc=2909

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2.

Gerver S, Chadborn T, Ibrahim F, et al. HIV-positive patient retention in the UK: high rate of loss to clinical follow-up among patients from a London clinic. 17th International AIDS Conference; August 5-8, 2008; Mexico City. Abstract TUAB0205.

http://www.aids2008.org/Pag/PSession.aspx?s=245

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3.

Taylor L, Gholam P, Delonget A, et al. Occult hepatitis B virus (HBV) and hepatitis C virus (HCV) viremia in women with and at-risk for HIV/AIDS. 17th International AIDS Conference; August 5-8, 2008; Mexico City. Abstract THAB0204.

http://www.aids2008.org/Pag/Abstracts.aspx?SID=236& AID=1155

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4.

Urbanus AT, van de Laar TJW, Schinkel J, et al. HCV is emerging as an STI among HIV-infected MSM: a threat to the MSM community. 17th International AIDS Conference; August 5-8, 2008; Mexico City. Abstract THPDC203.

http://www.aids2008.org/Pag/PSession.aspx?s=320

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5.

Lammers M, Davidovich U, Prins M, Stolteet I. Condom induced erectile dysfunction (COINED): a unique predictor of deliberate sexual risk. 17th International AIDS Conference; August 5-8, 2008; Mexico City. Abstract THPDC205.

http://www.aids2008.org/Pag/PSession.aspx?s=320

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Internet Resources
AIDS 2008 homepage. http://www.aids2008.org.