M. Kumi Smith

Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here?

Antiretroviral drugs that inhibit viral replication were expected to reduce transmission of HIV by lowering the concentration of HIV in the genital tract. In 11 of 13 observational studies, antiretroviral therapy (ART) provided to an HIV-infected index case led to greatly reduced transmission of HIV to a sexual partner. In the HPTN 052 randomised controlled trial, ART used in combination with condoms and counselling reduced HIV transmission by 96·4%. Evidence is growing that wider, earlier initiation of ART could reduce population-level incidence of HIV. However, the full benefits of this strategy will probably need universal access to very early ART and excellent adherence to treatment. Challenges to this approach are substantial. First, not all HIV-infected individuals can be located, especially people with acute and early infection who are most contagious. Second, the ability of ART to prevent HIV transmission in men who have sex with men (MSM) and people who use intravenous drugs has not been shown. Indeed, the stable or increased incidence of HIV in MSM in some communities where widespread use of ART has been established emphasises the concern that not enough is known about treatment as prevention for this crucial population. Third, although US guidelines call for immediate use of ART, such guidelines have not been embraced worldwide. Some experts do not believe that immediate or early ART is justified by present evidence, or that health-care infrastructure for this approach is sufficient. These concerns are very difficult to resolve. Ongoing community-based prospective trials of early ART are likely to help to establish the population-level benefit of ART, and-if successful-to galvanise treatment as prevention.

Antiviral agents and HIV prevention: controversies, conflicts, and consensus

Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.

Community viral load as a measure for assessment of HIV treatment as prevention

Community viral load, defined as an aggregation of individual viral loads of people infected with HIV in a specific community, has been proposed as a useful measure to monitor HIV treatment uptake and quantify its effect on transmission. The first reports of community viral load were published in 2009, and the measure was subsequently incorporated into the US National HIV/AIDS Strategy. Although intuitively an appealing strategy, measurement of community viral load has several theoretical limitations and biases that need further assessment, which can be grouped into four categories: issues of selection and measurement, the importance of HIV prevalence in determining the potential for ongoing HIV transmission, interpretation of community viral load and its effect on ongoing HIV transmission in a community, and the ecological fallacy (ie, ecological bias). These issues need careful assessment as community viral load is being considered as a public health measurement to assess the effect of HIV care on prevention.

HIV Treatment as Prevention: The Utility and Limitations of Ecological Observation

Results from several observational studies of HIV-discordant couples and a randomized controlled trial (HIV Prevention Trials Network 052) show that antiretroviral therapy (ART) can greatly reduce heterosexual HIV transmission in stable HIV-discordant couples. However, such data do not prove that ART will reduce HIV incidence at the population level. Observational investigations using ecological measures have been used to support the implementation of HIV treatment for the specific purpose of preventing transmission at the population level. Many of these studies note ecological associations between measures of increased ART uptake and decreased HIV transmission. Given the urgency of implementing HIV prevention measures, ecological studies must de facto be used to inform current strategies. However, the hypothesis that widespread ART can eliminate HIV infection may have raised expectations beyond what we may be able to achieve. Here we review and discuss the construct of the exposure and outcome measures and analysis methods used in ecological studies. By examining the strengths and weaknesses of ecological analyses, we aim to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.

Does ART prevent HIV transmission among MSM

Objective:To review the evidence for antiretroviral ‘treatment as prevention’ for HIV transmission among MSM. Methods:We reviewed studies that assess the biological plausibility that virally suppressive antiretroviral therapy (ART) reduces HIV infectiousness via anal intercourse and the epidemiologic evidence of whether ART has played a role in attenuating HIV incidence among MSM. Results:Although ART treatment among MSM is likely to provide some preventive benefit, it is unknown whether it will reduce HIV infectiousness via anal intercourse to the same extent as via penile–vaginal intercourse. Additional research is needed on the pharmacokinetic properties of specific antiretroviral agents in the gastrointestinal tract. Estimates of risk behaviors and the incidence of HIV among MSM before and after the introduction and expansion of ART suggest that the population-level protective benefits of ART may be attenuated by a number of factors, most notably, continuing or increasing frequency of condomless anal intercourse and incidence of other sexually transmitted infections (STIs). Additional studies are needed on the impact of ART on HIV sexual risk behaviors and transmission among MSM outside of developed countries in North America, western Europe, and Australia. Conclusion:The benefits of treatment as prevention for MSM are highly plausible, but not certain. In the face of these unknowns, treatment guidelines for earlier ART initiation should be considered within a combination prevention strategy that includes earlier diagnosis, expanded STI treatment, and structural and behavioral interventions.

Hepatitis C virus infection in China: an emerging public health issue

Hepatitis C virus now represents a global viral pandemic and is the fourth most commonly reported infectious disease in China. Information on Chinas national HCV epidemic was limited to cross ‐sectional seroprevalence studies of special populations, and a national surveillance effort had been launched to inform prevention and control. We analysed novel data from two national databases: (i) Chinas national medical HCV case report system and (ii) the national disease sentinel surveillance system. Between 1997 and 2012, reporting incidence of medical cases for HCV infection rose from 0.7 to 15.0 cases per 100 000 with the largest burden of disease concentrated among individuals over 35 years of age, rural residents and those tested as part of routine screening. Between 2010 and 2012, disease sentinel surveillance identified the highest HCV seropositive rates among persons who use drugs and haemodialysis patients, with far lower but not negligible rates among sexually active population. The concentration of cases among older age groups is consistent with past studies of age‐specific prevalence rates in Asia. Differences across regions and testing modes suggest diverse biological and social forces driving the spread of HCV in China. Surveillance data show ongoing transmission, particularly among persons who use drugs and persons undergoing invasive medical treatments, particularly haemodialysis. Improvements in case detection and data reporting systems will be critical for understanding current drivers of transmission and identifying key areas for prevention.

The detection and management of early HIV infection: A clinical and public health emergency

Abstract:This review considers the detection and management of early HIV infection (EHI), defined here as the first 6 months of infection. This phase is clinically important because a reservoir of infected cells formed in the individual renders HIV incurable, and the magnitude of viremia at the end of this period predicts the natural history of disease. Epidemiologically, it is critical because the very high viral load that typically accompanies early infection also makes infected individuals maximally contagious to their sexual partners. Future efforts to prevent HIV transmission with expanded testing and treatment may be compromised by elevated transmission risk earlier in the course of HIV infection, although the extent of this impact is yet unknown. Treatment as prevention efforts will nevertheless need to develop strategies to address testing, linkage to care, and treatment of EHI. Cost-effective and efficient identification of more persons with early HIV will depend on advancements in diagnostic technology and strengthened symptom-based screening strategies. Treatment for persons with EHI must balance individual health benefits and reduction of the risk of onward viral transmission. An increasing body of evidence supports the use of immediate antiretroviral therapy to treat EHI to maintain CD4 count and functionality, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. Although we can anticipate considerable challenges in identifying and linking to care persons in the earliest phases of HIV infection, there are many reasons to pursue this strategy.

Emerging Trends of HIV Drug Resistance in Chinese HIV-Infected Patients Receiving First-Line Highly Active Antiretroviral Therapy: A Systematic Review and Meta-Analysis

BACKGROUND Highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS-related morbidity and mortality through sustained suppression of human immunodeficiency virus (HIV) replication and reconstitution of the immune response. Settings like China that experienced rapid HAART rollout and relatively limited drug selection face considerable challenges in controlling HIV drug resistance (DR). METHODS We conducted a systematic review and meta-analysis to describe trends in emergent HIV DR to first-line HAART among Chinese HIV-infected patients, as reflected in the point prevalence of HIV DR at key points and fixed intervals after treatment initiation, using data from cohort studies and cross-sectional studies respectively. RESULTS Pooled prevalence of HIV DR from longitudinal cohorts studies was 10.79% (95% confidence interval [CI], 5.85%-19.07%) after 12 months of HAART and 80.58% (95% CI, 76.6%-84.02%) after 72 months of HAART. The HIV DR prevalence from cross-sectional studies was measured in treatment intervals; during the 0-12-month HAART treatment interval, the pooled prevalence of HIV DR was 11.1% (95% CI, 7.49%-16.14%), which increased to 22.92% at 61-72 months (95% CI, 9.45%-45.86%). Stratified analyses showed that patients receiving a didanosine-based regimen had higher HIV DR prevalence than those not taking didanosine (15.82% vs 4.97%). Patients infected through former plasma donation and those receiving AIDS treatment at village clinics had higher HIV DR prevalence than those infected through sexual transmission or treated at a county-level hospital. CONCLUSIONS Our findings indicate higher prevalence of HIV DR for patients with longer cumulative HAART exposure, highlighting important subgroups for future HIV DR surveillance and control.

The prevalence of HIV-1 drug resistance among antiretroviral treatment naïve individuals in mainland China: a meta-analysis.

Background Surveillance of drug resistance in antiretroviral treatment-naïve patients in China is needed to ensure optimal treatment outcomes and control of the human immunodeficiency virus (HIV) epidemic. Methods A systematic literature search was conducted in English and Chinese through PubMed (English), China National Knowledge Infrastructure (Chinese), Chinese Biomedical Literature Database (Chinese), and Wanfang (Chinese). Random effects models were used to calculate the pooled prevalence of transmitted drug resistance and subgroup analyses examined prevalence estimates across time periods, study locations, and study populations. Results Analysis of data from 71 studies (47 in Chinese and 24 in English) yielded a pooled prevalence of transmitted HIV drug resistance to any antiretroviral drug class of 3.64% (95% confidence interval [CI]: 3.00%–4.32%). Rates were significantly high at initial stage of free ART program from 2003 to 2005 (5.18%, 95%CI: 3.13%–7.63%), and were much lower among studies conducted in 2006–2008 (3.02%, 95%CI: 2.03%–4.16%). A slight increase was observed again in the most recent study period from 2009 to 2012 (3.68%, 95%CI: 2.78%–4.69%). Subgroup analysis revealed highest prevalence levels of transmitted drug resistance in Beijing city, and Henan and Hubei provinces (above 5%), and although differences in prevalence rates among risk groups were negligible, men who have sex with men were unique in their relatively large portion of protease inhibitor resistance, a second-line drug of limited availability in China. Conclusions Overall prevalence of transmitted HIV drug resistance in China is classified as “low” by the World Health Organization. However regional and temporal variability suggest a more complex epidemic for which closer HIV drug resistance surveillance is needed. A nationwide HIV drug resistance surveillance system to monitor both treatment-experienced and treatment-naïve patients will be a cornerstone to ensure the effectiveness of treatment scale-up, particularly as China seeks to expand a national policy of antiretroviral treatment as prevention.

Treatment to Prevent HIV Transmission in Serodiscordant Couples in Henan, China, 2006 to 2012

BACKGROUND Antiretroviral therapy (ART) administered in clinical trial settings virtually eliminates the sexual transmission of human immunodeficiency virus (HIV) in serodiscordant couples, but effectiveness of treatment as prevention in the community is debated. Conflicting results from previous analyses in a Chinese cohort underscore the importance of determining effectiveness of ART delivered in resource limited settings. METHODS All available years of data (2006-2012) from local disease control records of HIV patients and their seronegative spouses in Henan Province, China, were analyzed using marginal structural Cox models to estimate the effect of ART in the initially infected partner his or her partners HIV seroconversion risk. RESULTS We observed 157 seroconversion events in 4916 serosdiscordant couples, for an incidence rate of 0.59 cases per 100 person-years (PY) (95% confidence interval [CI], .51-.70). Of these, 84 occurred after the index partner had initiated ART (0.43/100PY; 95% CI, .35-.53) and 73, whereas index partners were untreated (5.87/100 PY; 95% CI, 4.65-7.42). In a marginal structural Cox model weighted for confounding and censoring, the hazard ratio (HR) for HIV transmission was 0.52 (95% CI, .34-.82). ART efficacy varied significantly by time period; least effective in the early phase from 2006 to 2008 (HR, 0.68; 95% CI, .34-1.36) but far more protective from 2009 onward (HR, 0.33; 95% CI, .20-.55). CONCLUSIONS ART can provide HIV-infected persons in resource-limited setting substantial protection against sexual transmission. Effectiveness in the Henan cohort appears to have increased over time, suggesting that quality of care and service infrastructure may be integral to successful use of treatment for prevention.