Preexposure prophylaxis for HIV infection: it's not as easy as ABC.
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Anti-HIV Agents↗
Biomedical subjects
Martin Fisher
Publications and source records attributed to Martin Fisher.
A case of multidrug resistant primary HIV infection with delayed CD4 T-cell count decline despite low viral load, treated with interleukin-2.
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Adult↗
A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study.
OBJECTIVE: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. DESIGN AND SETTING: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. PARTICIPANTS: Participants were 36 antiretroviral treatment naïve HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). INTERVENTIONS: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day (12 participants) or 9 MIU/day (12 participants) or no treatment (12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. OUTCOME MEASURES: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. RESULTS: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 (both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3-181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) (p = 0.008) and 128.4 cells/mm(3) (p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow-up (95% CI for difference, -0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. CONCLUSIONS: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels.
Journal Article↗
Analysis of protein solvent interactions in glucose dehydrogenase from the extreme halophile Haloferax mediterranei.
The structure of glucose dehydrogenase from the extreme halophile Haloferax mediterranei has been solved at 1.6-A resolution under crystallization conditions which closely mimic the "in vivo" intracellular environment. The decoration of the enzyme's surface with acidic residues is only partially neutralized by bound potassium counterions, which also appear to play a role in substrate binding. The surface shows the expected reduction in hydrophobic character, surprisingly not from changes associated with the loss of exposed hydrophobic residues but rather arising from a loss of lysines consistent with the genome wide-reduction of this residue in extreme halophiles. The structure reveals a highly ordered, multilayered solvation shell that can be seen to be organized into one dominant network covering much of the exposed surface accessible area to an extent not seen in almost any other protein structure solved. This finding is consistent with the requirement of the enzyme to form a protective shell in a dehydrating environment.
Glucose Dehydrogenases↗
UK Guideline for the use of post-exposure prophylaxis for HIV following sexual exposure.
We present the British Association for Sexual Health and HIV (BASHH) guidelines for post-exposure prophylaxis after sexual exposure (PEPSE) to HIV. This document includes a review of the current data to support the use of PEPSE, considers how to calculate the risks of HIV infection after a potential exposure, and provides recommendations on when PEPSE would and would not be considered. Other areas included are the possible impact on sexual behaviour, cost-effectiveness, and issues relating to service provision. Throughout the document, consideration is given to the place of PEPSE within the broader context of HIV prevention strategies and sexual health.
Acquired Immunodeficiency Syndrome↗
Clinical standards for the screening and management of acquired syphilis in HIV-positive adults.
These clinical standards for the screening and management of acquired syphilis in HIV-positive patients in the UK were first made available on the MSSVD website in February 2002. They have been updated by the 2006 UK National Guideline on the Sexual Health of People with HIV which is also published in this issue of the Journal [pp. 594-606]. Many of the recommendations remain in force and therefore the original document is published in full here.
Adult↗
Treatment of eating disorders in children, adolescents, and young adults.
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Adolescent↗
An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy.
OBJECTIVE: To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen. METHODOLOGY: A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load. RESULTS: A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50copies/ml (P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients (P=0.996) had responded to <50copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points. CONCLUSION: This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.
Adenine↗
The rate of viral rebound after attainment of an HIV load <50 copies/mL according to specific antiretroviral drugs in use: results from a multicenter cohort study.
BACKGROUND: Relatively few data are available on the association between the use of specific antiretroviral drugs and the rate of viral rebound in those attaining a viral load (VL) <50 copies/mL while receiving highly active antiretroviral therapy (HAART). METHODS: Patients achieving a VL <50 copies/mL for the first time while receiving HAART were followed until viral rebound (2 consecutive VLs >500 copies/mL). Pre-HAART antiretroviral-naive patients were analyzed separately from those with nucleoside reverse transcriptase inhibitor (NRTI) experience. RESULTS: Of 3565 suppressed antiretroviral-naive patients, 381 experienced viral rebound (rate, 6.26 events/100 person-years of follow-up [pyrs] [95% confidence interval {CI}, 5.63-6.89 events/100 pyrs]). For those receiving efavirenz, the rate was 4.08 (95% CI, 3.16-5.01) events/pyrs. Compared with this, the rebound rate for those receiving indinavir was 1.52 times higher (rate ratio [RR], 1.52 [95% CI, 0.82-2.84]). RRs (95% CIs) for other drugs were: soft-gel saquinavir, 0.54 (0.07-3.97); nelfinavir, 2.44 (1.68-3.54); indinavir/ritonavir, 1.96 (1.02-3.77); saquinavir/ritonavir, 1.12 (0.48-2.61); lopinavir/ritonavir, 1.23 (0.58-2.59); nevirapine, 1.53 (1.11-2.10); and abacavir, 2.03 (1.26-3.25). Of 810 NRTI-exposed patients, 145 experienced viral rebound (rate, 8.29 [95% CI, 6.94-9.64] events/pyrs). For those receiving efavirenz, the rate was 5.25 (95% CI, 3.11-8.30) events/pyrs. Compared with this, the RRs (95% CIs) were: indinavir, 1.75 (0.82-3.73); hard-gel saquinavir, 3.48 (0.36-33.37); nelfinavir, 2.64 (1.37-5.08); indinavir/ritonavir, 0.32 (0.04-2.49); saquinavir/ritonavir, 0.64 (0.23-1.80); nevirapine, 1.65 (0.90-3.02); and abacavir, 1.82 (0.73-4.52). CONCLUSIONS: We must make comparisons of antiretroviral outcomes in observational data with caution; however, our results suggest that, in those with VLs <50 copies/mL, certain drugs may be associated with higher rebound rates than others.
Adult↗
Crystallization and preliminary X-ray analysis of binary and ternary complexes of Haloferax mediterranei glucose dehydrogenase.
Haloferax mediterranei glucose dehydrogenase (EC 1.1.1.47) belongs to the medium-chain alcohol dehydrogenase superfamily and requires zinc for catalysis. In the majority of these family members, the catalytic zinc is tetrahedrally coordinated by the side chains of a cysteine, a histidine, a cysteine or glutamate and a water molecule. In H. mediterranei glucose dehydrogenase, sequence analysis indicates that the zinc coordination is different, with the invariant cysteine replaced by an aspartate residue. In order to analyse the significance of this replacement and to contribute to an understanding of the role of the metal ion in catalysis, a range of binary and ternary complexes of the wild-type and a D38C mutant protein have been crystallized. For most of the complexes, crystals belonging to space group I222 were obtained using sodium/potassium citrate as a precipitant. However, for the binary and non-productive ternary complexes with NADPH/Zn, it was necessary to replace the citrate with 2-methyl-2,4-pentanediol. Despite the radical change in conditions, the crystals thus formed were isomorphous.
Crystallization↗
Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice.
BACKGROUND: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice. METHODS: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI). RESULTS: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008). CONCLUSION: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.
Adult↗
Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study.
OBJECTIVES: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. DESIGN: Multicentre cohort study. SETTING: Six large HIV treatment centres in southeast England. PARTICIPANTS: All individuals seen for care between 1 January 1996 and 31 December 2002. MAIN OUTCOME MEASURES: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. RESULTS: Information is available on 16,593 individuals (13,378 (80.6%) male patients, 10,340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10,207 of the 16,593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of "viral load failure" with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. CONCLUSIONS: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.
Adolescent↗
Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice.
Tenofovir disoproxil fumarate (TDF) has been anecdotally associated with isolated hypophosphatemia (HP) as well as proximal tubular toxicity and renal dysfunction in which HP has consistently been a feature. Consequently, routine phosphate measurements in TDF recipients have been recommended. We identified and compared the frequency of HP in TDF recipients with that in non-TDF recipients; assessed the reproducibility of HP; identified the incidence of renal dysfunction in hypophosphatemic patients; and evaluated associations between HP and host, HIV infection, or treatment factors. This prospective observational study measured serum phosphate, urea, and creatinine in HIV-positive individuals among the following treatment groups: TDF-containing highly active antiretroviral therapy (HAART, group A), TDF-sparing HAART (group B), HAART naive (group C), and off HAART but treatment experienced (group D). Phosphate measurements were obtained in 252 patients. Seventy-two percent of patients prescribed TDF received a phosphate measurement. The frequency of HP in groups A, B, C, and D was 31%, 22%, 10%, and 14%, respectively. Seventy-eight percent of phosphate measurements were reproducible. Kaletra (P = 0.016) administration and duration of antiretroviral therapy (P = 0.023) were independently associated with HP, but elevated creatinine and urea or use of TDF was not. The etiology of HP seems to be multifactorial and unrelated to TDF or renal dysfunction. This questions the utility of routine phosphate testing, in isolation, in TDF recipients.
Adenine↗
Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections.
OBJECTIVE: To study primary HIV-1 infections (PHI) using molecular and epidemiological approaches in order to assess correlates of transmission in this population. METHODS: Individuals with PHI were recruited prospectively from a discrete cohort of 1235 individuals under follow-up in a well-defined geographical area between 1999 and 2003. PHI was diagnosed by one of the following: negative HIV antibody test within 18 months, evolving antibody response, or application of the serological testing algorithm for recent HIV seroconversion. The pol gene was sequenced to identify genotypic resistance and facilitate molecular epidemiological analysis. Clinical data were collected and linked in an irretrievable fashion when informed consent was obtained. RESULTS: A total of 103 individuals with PHI diagnosed between 1999 and 2003 were included in the study; 99 (96%) were male and 90 (91%) were men who have sex with men. Viruses from 35 out of 103 (34%) appeared within 15 phylogenetically related clusters. Significant associations with clustering were: young age, high CD4 cell count, number of sexual contacts, and unprotected anal intercourse (UAI) in the 3 months before diagnosis (P < 0.05 for all). High rates of acute sexually transmitted infections (STI) were observed in both groups with a trend towards higher rates in those individuals with viruses within a cluster (42.9 versus 27.9%; P = 0.13). CONCLUSION: High rates of partner change, UAI and STI are factors that facilitate onward transmission during PHI. More active identification of individuals during PHI, the management of STI and highly active antiretroviral therapy may all be useful methods to break transmission networks.
Acute Disease↗
A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study).
BACKGROUND: Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations. METHODS: Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out. RESULTS: A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment. CONCLUSIONS: No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).
Alkynes↗
Long-term persistence of primary genotypic resistance after HIV-1 seroconversion.
Primary infection with drug-resistant HIV-1 is well documented. We have followed up patients infected with such viruses to determine the stability of resistance-associated mutations. Fourteen patients who experienced primary infection with genotypic evidence of resistance were followed for up to 3 years. Drug resistance-associated mutations persisted over time in most patients studied. In particular, M41L, T69N, K103N, and T215 variants within reverse transcriptase (RT) and multidrug resistance demonstrated little reversion to wild-type virus. By contrast, Y181C and K219Q in RT, occurring alone, disappeared within 25 and 9 months, respectively. Multidrug resistance in 2 patients was found to be stable for up to 18 months, the maximum period studied. We conclude that certain resistance-associated mutations are highly stable and these data support the recommendation that all new HIV diagnoses in areas where primary resistance may occur should undergo genotyping irrespective of whether the date of seroconversion is known.
Anti-HIV Agents↗
Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression.
BACKGROUND: It is currently unclear whether the tendency for viral rebound in patients with viral load < 50 copies/ml differs according to the specific drug regimen being used. METHODS: To follow 2120 patients in EuroSIDA who had attained < 50 copies/ml on highly active antiretroviral therapy (HAART), without previously virologically failing HAART. RESULTS: The rate of viral rebound (two consecutive values > 400 copies/ml) was 4.9/100 person-years [95% confidence interval (CI), 4.0-5.8] for patients who were naive pre-HAART and 8.0/100 person-years (95% CI, 7.0-9.0) for those who were experienced with nucleoside analogue reverse transcriptase inhibitors (NRTI) pre-HAART. The rate of rebound was significantly higher in those taking nelfinavir than in those taking efavirenz, both in patients who were naive pre-HAART and those who were NRTI experienced [adjusted rate ratios, 2.83 (95% CI, 1.51-5.31) and 2.86 (95% CI, 1.65-5.00), respectively]. Among patients who were naive pre-HAART, those on abacavir had no evidence of a raised risk of viral rebound (adjusted rate ratio 1.17; 95% CI, 0.51-2.69), but in those with pre-HAART NRTI experience the rate was markedly raised (adjusted rate ratio, 4.48; 95% CI, 2.51-8.00). A similar picture was seen when comparing those on nevirapine with those on efavirenz, although the elevated rate ratio in pre-HAART experienced patients was of lower magnitude (adjusted rate ratio, 1.93). There was no strong evidence that rebound rates differed significantly for any NRTI pairs compared with zidovudine/lamivudine. CONCLUSION: Viral rebound rates in patients who have attained < 50 copies/ml appear to differ according to the specific drugs being used.
Adult↗
Do patients who are infected with drug-resistant HIV have a different CD4 cell decline after seroconversion? An exploratory analysis in the UK Register of HIV Seroconverters.
Using data from the UK Register of HIV Sero-converters, we compared the rate of CD4 cell decline in antiretroviral-naive individuals with and without evidence of transmitted drug resistance (TDR). Although there was a suggestion that CD4 cell decline in the first year after seroconversion was faster in those with TDR,there was no evidence of a difference in the rate of decline thereafter. The virological and host determinants of this possible phenomenon are worth further exploration.
Adult↗