Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

BACKGROUND: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.

Seroprevalence of HIV, hepatitis b, and hepatitis c among opioid drug users on methadone treatment in the netherlands.

BACKGROUND: Injecting drug users (IDU) remain an important population at risk for blood-borne infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). In the Netherlands, a program is being implemented to offer annual voluntary screening for these infections to opioid drug users (ODUs) screened in methadone care. At two care sites where the program is now operating, our study aimed to estimate the seroprevalence among ODUs screened for HIV, HBV and HCV; to evaluate HBV vaccination coverage; and to assess the feasibility of monitoring seroprevalence trends by using routine annual screening data. METHODS: Opioid drug users on methadone treatment are routinely offered voluntary screening for infectious diseases such as HIV, HBV and HCV. Data on uptake and outcome of anti-HIV, anti-HBc, and anti-HCV screening among ODUs receiving methadone were obtained from two regions: Amsterdam from 2004 to 2008 and Heerlen from 2003 to 2009. FINDINGS: Annual screening uptake for HIV, HBV and HCV varied from 34 to 69%, depending on disease and screening site. Of users screened, 2.5% were HIV-positive in Amsterdam and 11% in Heerlen; 26% were HCV-positive in Amsterdam and 61% in Heerlen. Of those screened for HBV, evidence of current or previous infection (anti-HBc) was found among 33% in Amsterdam and 48% in Heerlen. In Amsterdam, 92% were fully vaccinated for HBV versus 45% in Heerlen. CONCLUSION: Annual screening for infectious diseases in all ODUs in methadone care is not fully implemented in the Netherlands. On average, more than half of the ODUs in methadone care in Heerlen and Amsterdam were screened for HIV, HBV and HCV. In addition, screening data indicate that HBV vaccination uptake was rather high. While the HIV prevalence among these ODUs was relatively low compared to other drug-using populations, the high HCV prevalence among this group underscores the need to expand annual screening and interventions to monitor HIV, HBV and HCV in the opioid drug-using population.

Epidemiological impact and cost-effectiveness of providing long-acting pre-exposure prophylaxis to injectable contraceptive users for HIV prevention in South Africa: a modelling study.

INTRODUCTION: Although pre-exposure prophylaxis (PrEP.) is an efficacious HIV prevention strategy, its preventive benefit has not been shown among young women in sub-Saharan Africa, likely due to non-adherence. Adherence may be improved with the use of injectable long-acting PrEP methods currently being developed. We hypothesize that providing long-acting PrEP to women using injectable contraceptives, the most frequently used contraceptive method in South Africa, could improve adherence to PrEP, result in a reduction of new HIV infections, and be a relatively easy-to-reach target population. In this modelling study, we assessed the epidemiological impact and cost-effectiveness of providing long-acting PrEP to injectable contraceptive users in Limpopo, South Africa. METHODS: We developed a deterministic mathematical model calibrated to the HIV epidemic in Limpopo. Long-acting PrEP was provided to 50% of HIV negative injectable contraceptive users in 2018 and scaled-up over two years. We estimated the number of HIV infections that could be averted by 2030 and the drug price of long-acting PrEP for which this intervention would be cost-effective over a time horizon of 40 years, from a healthcare payer perspective. In the base-case scenario we assumed long-acting PrEP is 75% effective in preventing HIV infections and 85% of infected individuals are on antiretroviral drug therapy (ART) by 2030. In sensitivity analyses we adjusted PrEP effectiveness and ART coverage. Costs between $519 and $1119 per disability-adjusted life-year (DALY) averted were considered potentially cost-effective, and <$519 as cost-effective. RESULTS: Without long-acting injectable PrEP, 224,000 (interquartile range 176,000 to 271,000) new infections will occur by 2030; use of long-acting injectable PrEP could prevent 21,000 (17,000 to 26,000) or 9.8% (8.9% to 10.6%) new HIV infections by 2030 (including 6000 (4000 to 7000) in men). Long-acting PrEP would prevent 34,000 (29,000 to 39,000) or 12,000 (8000 to 15,000) at 75% and 95% ART coverage by 2030 respectively. To be considered potentially cost-effective the annual long-acting PrEP drug price should be <$16, and/or ART coverage remains at <85% in 2030. CONCLUSIONS: Providing long-acting PrEP to injectable contraceptive users in Limpopo is only potentially cost-effective when long-acting PrEP drug prices are low. If low prices are not feasible, providing long-acting PrEP only to women at high risk of HIV infection will become important.

Treatment response to ritonavir-boosted tipranavir versus ritonavir-boosted lopinavir in HIV-1 patients with higher lopinavir mutation scores.

Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.

Ending AIDS as a public health threat by 2030: Scientific Developments from the 2016 INTEREST Conference in Yaoundé, Cameroon.

The underpinning theme of the 2016 INTEREST Conference held in Yaoundé, Cameroon, 3-6 May 2016 was ending AIDS as a public health threat by 2030. Focused primarily on HIV treatment, pathogenesis and prevention research in resource-limited settings, the conference attracted 369 active delegates from 34 countries, of which 22 were in Africa. Presentations on treatment optimization, acquired drug resistance, care of children and adolescents, laboratory monitoring and diagnostics, implementation challenges, HIV prevention, key populations, vaccine and cure, hepatitis C, mHealth, financing the HIV response and emerging pathogens, were accompanied by oral, mini-oral and poster presentations. Spirited plenary debates on the UNAIDS 90-90-90 treatment cascade goal and on antiretroviral pre-exposure prophylaxis took place. Joep Lange career guidance sessions and grantspersonship sessions attracted early career researchers. At the closing ceremony, the Yaoundé Declaration called on African governments; UNAIDS; development, bilateral, and multilateral partners; and civil society to adopt urgent and sustained approaches to end HIV by 2030.

Second European Round Table on the Future Management of HIV: 10-11 October 2014, Barcelona, Spain.

The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects.

Identifying potential survival strategies of HIV-1 through virus-host protein interaction networks.

BACKGROUND: The National Institute of Allergy and Infectious Diseases has launched the HIV-1 Human Protein Interaction Database in an effort to catalogue all published interactions between HIV-1 and human proteins. In order to systematically investigate these interactions functionally and dynamically, we have constructed an HIV-1 human protein interaction network. This network was analyzed for important proteins and processes that are specific for the HIV life-cycle. In order to expose viral strategies, network motif analysis was carried out showing reoccurring patterns in virus-host dynamics. RESULTS: Our analyses show that human proteins interacting with HIV form a densely connected and central sub-network within the total human protein interaction network. The evaluation of this sub-network for connectivity and centrality resulted in a set of proteins essential for the HIV life-cycle. Remarkably, we were able to associate proteins involved in RNA polymerase II transcription with hubs and proteasome formation with bottlenecks. Inferred network motifs show significant over-representation of positive and negative feedback patterns between virus and host. Strikingly, such patterns have never been reported in combined virus-host systems. CONCLUSIONS: HIV infection results in a reprioritization of cellular processes reflected by an increase in the relative importance of transcriptional machinery and proteasome formation. We conclude that during the evolution of HIV, some patterns of interaction have been selected for resulting in a system where virus proteins preferably interact with central human proteins for direct control and with proteasomal proteins for indirect control over the cellular processes. Finally, the patterns described by network motifs illustrate how virus and host interact with one another.

Novel mechanisms of HIV protease inhibitor resistance.

PURPOSE OF REVIEW: Several alternative mechanisms that cause protease inhibitor resistance have been proposed. A summary of the proposed mechanisms and the status regarding their clinical relevance is given. RECENT FINDINGS: At this moment only changes in the cleavage sites of protease (either alone or in the background of protease mutations) have been associated with phenotypic changes in IC50 and virological failure. SUMMARY: Further studies are necessary to unravel the mechanism, the clinical relevance and potential effect of transmission of these cleavage site changes.