Barry Peters

British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008

This summary document is an update to the full British HIV Association (BHIVA) Treatment Guidelines published in HIV Medicine in July 2005 (Volume 6, Supplement 2). Only the ‘What to start with’ and ‘Treatment-experienced patients’ sections have been completely rewritten. The tables of recommendations (Tables 1–7) have also been updated to include new data. Please refer to the full guidelines for more information.

Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial.

Low levels of vitamin D are reported in HIV-infected individuals. In HIV-negative people, low vitamin D levels have been associated with an increased risk of cardiovascular disease and cancer and with worse survival. The MONET trial recruited 256 European patients with HIV RNA <50 copies/ml at screening, while taking either NNRTI- or PI-based HAART. Patients were switched to DRV/r 800/100u2009mg once daily, either as monotherapy or with two NRTIs. In all, 221 patients were measured for 25-hydroxyvitamin D at a central laboratory before randomized treatment started and at week 96. Multiple regression was used to correlate vitamin D levels with gender, season, ethnic group, treatment group, and use of antiretrovirals. Overall, 80% of patients were male and 91% were white, with a mean age of 44 years. At screening, 170/221 (77%) patients had vitamin D deficiency (<50u2009nmol/liter). At the screening visit, lower vitamin D levels were significantly associated with calendar month (pu2009=u20090.0067), black ethnicity (pu2009=u20090.013), use of efavirenz (pu2009=u20090.0062), and use of zidovudine (pu2009=u20090.015). Mean vitamin D levels were lowest from January to April (meanu2009=u200935.8u2009nmol/liter) and highest in September (meanu2009=u200945.4u2009nmol/liter). Increases in vitamin D between screening and week 96 were significantly greater for patients who discontinued efavirenz or zidovudine before the MONET trial versus those who stopped other antiretrovirals. At screening, lower vitamin D levels were associated with season, race, and use of efavirenz and/or zidovudine. Switching from efavirenz and/or zidovudine to darunavir/ritonavir during the trial led to increases in vitamin D levels. Routine screening of HIV-positive patients for vitamin D should be considered and the optimal management further defined.

Effect of heterosexual intercourse on mucosal alloimmunisation and resistance to HIV-1 infection

BACKGROUNDnUnprotected sexual intercourse between regular heterosexual partners could elicit alloimmune responses that might be associated with inhibition of in-vitro HIV-1 infectivity. We investigated this hypothesis in people practising unprotected sex and those using protection.nnnMETHODSnWe recruited 82 participants from an outpatient genitourinary medicine clinic. 29 monogamous heterosexual couples having unprotected sex; and 15 women and 10 men having condom protected or no sex. We used the mixed leucocyte reaction (MLR), stimulating one partners peripheral blood mononuclear cells (PBMC) with the other partners irradiated PBMC and compared the resulting response with control PBMC. We studied resistance to HIV-1 infection by challenging activated CD4-positive T cells with CCR5-binding and CXCR4-binding HIV-1 strains, and comparing the infectivity in participants having unprotected sex with those practising protected sex. We used the correlation coefficient to establish the significance of the relation between MLR and HIV-1 infectivity.nnnFINDINGSnWe recorded a significant increase in the stimulation indices in PBMC from women whose cells were stimulated with irradiated PBMC (2%, 10%, or 50%) from their regular partners. The mean with 10% partners cells was 8.6 (SD 7.7), compared with those from unrelated cells (4.7 [3.9], p=0.009). Significant alloimmune responses were also seen in corresponding male partners, but only with 50% stimulating cells (p=0.013). Dose-dependent inhibition of activated CD4-positive T cells to HIV-1 infection with both binding strains was noted in vitro in women practising unprotected intercourse, compared with those having protected sex or having no sex for more than 1 year. Highly significant differences were found for CCR5 (p=0.0001) and for CXCR4 (p=0.001) strains of HIV-1 at all four virus-concentrations. Male partners also showed in-vitro inhibition of HIV-1 but this was less than that in women.nnnINTERPRETATIONnUnprotected sexual intercourse might result in alloimmunisation stimulated by HLA antigens in seminal or cervicovaginal fluid. Mucosal alloimmunisation may reduce infection by HIV-1, and the role of such immunisation in preventive and therapeutic vaccination should be investigated.

Treatment issues for HIV+ Africans in London.

Black Africans are the second largest group of HIV/AIDS service users in London, UK. They are distinguished from other patient groups by their delay in access to services and appear to have a lower uptake of antiretroviral therapies. This study explores the treatment issues concerning black Africans which may affect their uptake of therapies. Issues raised included questions about if and when to start treatment, fears of side-effects both short and long term, awareness of the current uncertainties surrounding combination therapies and concerns about how to achieve compliance. The social circumstances of HIV positive black Africans living in London together with differences in cultural beliefs and experience of health care in the UK give rise to particular treatment concerns. These concerns include the fear of being experimented upon, lack of confidence in drugs tested only on Caucasians, distrust of the medical profession and fears of discrimination. Efforts to encourage the uptake of antiretroviral therapies by black Africans in Britain must take into account the particular experiences, fears and concerns of this patient group.

Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors

ABSTRACT Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.

Disseminated strongyloidiasis in AIDS: uncommon but important.

Disseminated Strongyloides stercoralis infection is a rare and severe but treatable complication of AIDS. We present a case where this infection was successfully treated and review the available literature. Cases may present many years after they have left an area endemic for Strongyloides infection, emphasizing the need for a full travel history. Symptoms are typically gastrointestinal and pulmonary, with infiltrates often seen on chest radiography. Diagnosis requires stool examination and biopsy of affected sites. Treatment with repeated courses of thiabendazole (25 mg/kg twice daily for 5 days) was successful in our case, but maintenance regimens have not yet been defined. The relative rarity of this complication of AIDS suggests that, where both infections are present, disseminated strongyloidiasis only arises either when HIV-induced immunodeficiency is profound or, possibly, when it is accompanied by impaired granulopoiesis.

Interaction between the CCR5 chemokine receptors and microbial HSP70

Evidence is presented that the microbial 70‐kD heat shock protein (HSP70) binds to CCR5 chemokine receptors in CCR5‐transfected cell lines and in primary human cells. Significant CCR5‐mediated calcium mobilization was stimulated by HSP70 and inhibited with TAKu2004779, which is a specific CCR5 antagonist. HSP70‐mediated activation of the p38 MAPK phosphorylation signaling pathway was also demonstrated in CCR5‐transfected HEK 293 cells. Direct binding of three extracellular peptides of CCR5 to HSP70 was demonstrated by surface plasmon resonance. Functional evidence of an interaction between HSP70, CCR5 and CD40 was shown by enhanced production of CCL5 by HEK 293 cells transfected with both CD40 and CCR5. Primary monocyte‐derived immature DC stimulated with HSP70 produced IL‐12 p40, which showed dose‐dependent inhibition of >90% on treatment with both TAK 779 and anti‐CD40 mAb. Stimulation of IL‐12 p40 or TNF‐α by HSP70 was related to the differential cell surface expression of CCR5 in primary human immature and mature DC, and those with the homozygous ▵▵32 CCR5 mutation. These findings may be of significance in the interaction between HSP70 and immune responses of CCR5+ T cells in HIV‐1 infection, as well as in inflammatory bowel disease.

The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml.

ObjectivesTo determine the prevalence and prognostic significance of intermittent viraemia (IV) in patients who attained an undetectable viral load (VL) < 400 copies/ml within 6 months on highly active antiretroviral therapy (HAART). MethodsRetrospective analysis of viral load rebound ⩾ 400 copies/ml and CD4 cell counts rise for 765 patients followed for ⩾ 12 months following initial VL undetectability, comparing the 226 (29.5%) who maintained an undetectable VL for > 1 year from initiation of HAART and 122 (15.9%) who had one or more episodes of IV. Genotypic resistance was evaluated at the time of the first episode of IV ⩾ 2000 copies/ml. ResultsPatients with IV had a threefold higher rate of sustained virological rebound [hazards ratio (HR), 3.15; 95% confidence interval (CI), 1.72–5.77;P < 0.001). For patients with and without IV, the Kaplan–Meier estimates at 24 and 36 months after initiation of HAART were 19.3% (95% CI, 8.9–21.5) versus 7.7% (95% CI, 4.5–13.0) and 31.6% (95% CI, 21.8–44.2) versus 12.9% (95% CI, 7.5–21.5), respectively (P < 0.001). The median CD4 cell count rise at 18 and 24 months was significantly lower in those with IV than in those without: 138 [interquartile range (IQR), 58–221] versus 224 × 106 cells/l (IQR, 119–357) (P = 0.0001) and 200 (IQR, 89–294) versus 260 × 106 cells/l (IQR, 125–384) (P = 0.003), respectively. In a subgroup of 16 patients, genotypic resistance mutations were found in the reverse transcriptase gene for five (31%) and in the protease gene in one. A probable contributing factor/event was identified for most patients with IV, such as poor adherence (42.6%), intercurrent infection (26.2%) or drug interaction (6.8%). ConclusionsPatients with IV > 400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.

Insulin resistance and HIV infection: a review.

Highly active antiretroviral therapy (HAART) has markedly improved the prognosis of people with HIV infection. However, there are long‐term side effects associated with HAART. Alterations in metabolic parameters are common and include hyperlipidaemia and insulin resistance (IR), either in isolation or as part of the lipodystrophy and metabolic syndromes. Insulin resistance is common in HIV‐infected people, particularly among those being treated with protease inhibitor therapy. The prevalence of hyperglycaemia and diabetes mellitus is significantly higher in people with HIV infection being treated with antiretrovirals (ARVs), as compared with the general population. Hyperglycaemia is an important risk factor for the development of secondary pathology, including cardiovascular disease. It is therefore important to consider the effects of IR in HIV‐infected individuals, and take measures to prevent or manage it appropriately. There is limited evidence for the benefit of pharmacological interventions for IR alone although the metabolic changes and body shape changes of lipodystrophy might benefit from the combined use of metformin with exercise. At present, therefore, it is best to concentrate on preventative measures, including lifestyle modification, the careful selection of ARV drugs, and changing drug combinations where appropriate.