By Q. Bernado. Abraham Baldwin Agricultural College.

Since HIV could theoretically remain undetected order erectafil 20 mg with visa, sperm washing is currently regarded as a very effective risk reduc- tion cheap 20 mg erectafil with amex, although not risk-free erectafil 20 mg on-line. Most of the European centers that offer assisted reproduction to HIV-discordant couples are part of the CREATHE network order erectafil 20mg, which aims to optimize treatment and safety of the methods as well as to compile an extensive database. Compiled data from several centers hint on the safety and reliability of sperm washing (Bujan 2007). Pre-Exposure Prophylaxis (PrEP) Even before the FDA approval of Truvada as the first antiretroviral agent for the prevention of HIV transmission through sexual intercourse, PrEP before periovula- tory unprotected intercourse was an option for serodiscordant couples in some coun- tries. Couples abstain from condom use only during the woman’s fertile days. HIV and Wanting to be a Parent 551 Preconditions are an effectively suppressed viral load, the exclusion of sexually trans- mitted diseases, and unimpaired fertility status of both partners. Data from Switzerland and Germany shows high acceptance in couples. No case of HIV trans- mission has been reported in 53 couples, the pregnancy rate was 75% (Vernazza 2011). A growing number of studies shows the feasibility of this approach, especially in resource-limited settings (Adenji 2013, Whetham 2013). The fertility of HIV-neg- ative men does not seem to be impaired by taking PrEP (Were 2014). Up to now, there is no evidence that PrEP further reduces the already negligible risk of infection when the viral load of the HIV+ partner is effectively suppressed. Nevertheless, some couples prefer this option because it increases their feeling of safety. Female HIV infection For many HIV+ women having a child now is an important part of planning for the future (Fiore 2008, Loutfy 2009). In France 32% of the HIV+ women of reproductive age want to become mothers (Heard 2007). Treatment and care during pregnancy should be carried out according to the pre- vailing national or international guidelines (Fakoya 2008, DAIG 2011, Loutfy 2012). In some European countries reproductive options for women with unimpaired fer- tility include natural conception on the basis of the EKAF Statement as well as self- insemination, while self-insemination is still seen as the safest procedure. Couples who decide for natural conception should undergo screening to exclude STDs. The transmission risk might be further reduced when the intercourse without condoms is limited to the time of ovulation. Women should be advised on the impor- tance of adherence and regular checks of the viral load (Fakoya 2008). If a woman is not taking ART, the viral load is not successfully suppressed, or concerns about the remaining risk are strong, self-insemination may be the method of choice. In some cases, ovarian stimulation may be advisable. This, however, requires highly qualified supervision to avoid multiple gestations. A simple inexpensive way of determining whether the cycles are ovulatory, helpful in women who have regular cycles, is a basal temperature chart beginning about three months before the first self-insemination. At the time of ovulation, couples can either have protected intercourse with a sper- micide-free condom and introduce the ejaculate into the vaginal cavity afterwards, or the ejaculate can be vaginally injected using a syringe or applied with a diaphragm or portio cap. Thus the conception remains within the private sphere of the couple. After 6–12 months of unsuccessful self-insemination, the couple should have further fertility investigations with a view to assisted conception. Should the couple experience problems with self-insemination, intrauterine insemination (IUI) can be considered. HIV-specific and infective diagnostics are recommended. If no pregnancy has occurred over a period of 6–12 months (or earlier, if the couple so wishes) fertility diagnostics should be carried out (Table 1). If there are indicators of reduced fertil- ity in one or both partners, fertility diagnostics might be carried out at an earlier stage in the counselling process. Fertility disorders In some cases, women will only be able to conceive by intercourse without condom or self insemination. Dependent on the fertility status of both partners, IVF and ICSI can be considered as methods of choice. Fertility disorders in HIV+ women seem to have a higher prevalence than in an age- matched negative population (Ohl 2005, Gingelmaier 2010) and might lead to a 552 Women and Children lower success rate of assisted reproduction (Coll 2006) although data show some conflicting results. Reasons might be infection of the upper genital tract (Sobel 2000), surgery due to cervical intraepithelial neoplasia (Gilles 2005) or a depletion of mito- chondrial DNA in the oocytes (Garrabou 2006, Lopez 2008). Data reported from a program in Strasbourg indicated infertility problems in most HIV+ women. IVF and ICSI were far more effective than IUI (Ohl 2005). In the Barcelona program, Coll (2006) observed a decreased pregnancy rate after IVF com- pared to age-matched HIV-negative controls and HIV+ women who received donated oocytes. Results indicated a decreased ovarian response to hyperstimulation. A slightly impaired ovarian response to stimulation during 66 ICSI cycles in 29 HIV+ women was also described by Terriou (2005). Martinet (2006) found no difference in ovarian response between HIV+ and HIV-negative women in Brussels. Data concerning a possible association between ART and fertility disorders in women is limited (van Leeuwen 2006). Although assisted reproduction for seropositive women with fertility disorders is offered in centers in various European countries as well as the US, access to assisted reproduction often is still more limited for women than for men. HIV infection of both partners A growing number of HIV-concordant couples are now seeking reproductive coun- seling. In some centers, these couples are also accepted for reproductive treatment in case of fertility disorders. If both partners are on effective ART and there are no fertility disorders present, timed unprotected intercourse can be the method of choice. The discussion pertaining to the transmission of mutated drug-resistant virus between partners is still ongoing. Following a recent review (Redd 2013), the trans- mission rate is higher than previously assumed, showing an incidence rate of up to 7. Couples should be offered the same range of fertility counseling and screening as HIV-discordant couples. The current health of each partner should be carefully eval- uated with a full report from their HIV physician. Psychosocial aspects Experiences from more than a decade of counselling show the importance of offe- ring professional psychosocial support to couples planning to conceive, especially if reproductive assistance is necessary. Accepting the desire to become parents and dealing with the underlying motives as well as the psychosocial situation in an empa- thic way enables couples to see obstacles as well as to develop alternative perspecti- ves if this wish cannot be realized. Frustration, strains and disappointment may accompany unsuccessful treatment cycles or premature termination of pregnancy. Psychiatric co-morbidities in one or both partners (i. Professional diagnosis and support is necessary in these cases. Often, the central importance of the wish for parenthood of many migrant couples is overlooked in the medical and psychosocial counselling system. Language or communication difficulties on both sides, ignorance of different cultural back- grounds and lack of acceptance of other life-styles can lead to feelings of discrimi- nation, isolation, helplessness or despair in couples. Issues concerning the welfare of the child should be openly discussed during repro- ductive counselling. Many couples are concerned about a potential negative effect of antiretroviral drugs on their offspring. Severe impairment of the health of the pro- spective parents might lead to concerns for the future well-being of the child.

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As the life expectancy of HIV+ individuals in the developed world now comes close to that of the general population (May 2014) purchase online erectafil, the prevalence of HAND has risen to 628 Interdisciplinary Medicine 20-50% (Sacktor 2002 discount erectafil uk, Heaton 2010) purchase erectafil 20 mg otc. With ART 20mg erectafil, the prevalence of severe cases has decreased while that of the minor variants has increased (Heaton 2011). Among indi- viduals in the WHO/CDC clinical stage A, however, a slight to moderate impairment is more frequent than in the pre-HAART-era. Longitudinal cohort observations have shown that many patients with asymptomatic neurocognitive impairment (ANI), even with suppressed plasma viral load, will eventually develop symptomatic NCI (Cole 2007, Grant 2014). Patients who were diagnosed and treated early after infec- tion had a low prevalence of NCI (Crum-Cianflone 2013). A study of treated subjects with initially low but increasing CD4 T cell counts showed some improvement of cognitive function, but this remained worse than that of an HIV-negative control group (Mc Cutchan 2007). Frequent subjective complaints of reduced cognitive performance with and without objective correlates on formal neuropsychological testing have been found in many patients with longstanding suppression of plasma viral load (Simioni 2010). HAND is associated with a shortened survival (Sevigny 2007) and with poor medication adherence (Albert 1999). It is generally accepted that HAND, in untreated patients, at least in its more severe stages, is a treatable condition. However, the extent and sustainability of the effects of ART on cerebral function are still unclear. Progressive, clinically relevant, and, at times, fluctuating neurocognitive impairment may occur in patients on suppressive ART (Brew 2004, Antinori 2007, Canestri 2010, Peluso 2012). HIV-1-associated dementia (HAD) as the most severe HAND manifestation is now rare on ART (Price 2008). However, more subtle but, with regard to working performance, significant dysfunction may be seen in everyday clinical practice, and it now occurs at earlier stages of HIV-induced immunosuppression (Sacktor 2001, Dore 2003). In the pre-HAART era, the time course of the CSF and plasma viral load and the current CD4 T cell count were predictors of HAND, but this has now changed. Longitudinal studies in ART-treated subjects without dementia show low nadir CD4 T cell counts, previous AIDS, longer duration of HIV infection, low educational status, older age, plasma levels of TNF-alpha and MCP-1, illicit drug use, and comorbidity in general to be predictors for the development of HAND (Robertson 2007, Sevigny 2007, Tozzi 2007, Bhaskaran 2008, Heaton 2010, Mind Exchange Group 2013). The occurrence and/or persistence of HAND, despite effective suppression of plasma viral replication, might be associated with chronic immune activation within the CNS, as suggested by persistently elevated levels of neopterin and anti-MOG antibodies in the CSF (Eden 2007, Lackner 2010), and by microglial activation on brain positron emission tomography (PET) (Garvey 2013). This observation might suggest some “uncoupling” of mechanisms within the CNS from those in the hematolymphatic compartments. Contrary to earlier estimates, HCV coinfection seems not to confer NCI (Clifford 2015). Cases of severe HAD with high levels of CSF viral load were observed in patients with well-suppressed plasma viral load (“viral escape”) on ART (Venkataramana 2006, Canestri 2010, Peluso 2012). In an autopsied patient, numerous CD8-positive lym- phocytes were found in the perivascular spaces and the parenchyma, partly in close spatial association with neurons. This condition may be interpreted as an immune reconstitution phenomenon directed against HIV itself (Venkataramana 2006). Clinical manifestation HAND is considered to be a subcortical dementia. With the introduction of ART, signs of cortical involvement and memory impairment have become more promi- nent, while motor signs have become less important (Heaton 2011). HIV-1-associated Neurocognitive Disorder (HAND) and Myelopathy 629 HAND emerges over the course of weeks and months. Acutely developing symptoms point to another etiology. Fever, exhaustion, the effects of tranquilizers, reduced physical condition and even major depression may all mimic dementia. In these cases, diagnosis of HAND can only be made after repeated examinations when the condition mimicking dementia has improved. Expressing complaints about neurocognitive dysfunction is not equivalent to actu- ally being impaired. Patients in whom cognitive testing actually demonstrates NCI tend to underestimate the degree of their dysfunction, while the opposite is true for patients with depression (Thames 2011). This is why a history given by informants close to the patient is important. Typical complaints are slowing of reasoning, for- getfulness, difficulties concentrating, lack of energy, mild depressive symptoms and emotional blunting (Tables 2 and 3). In terms of clinical findings, impairment of alertness, neck stiffness, focal or lateralizing neurological signs (e. Psychotic symptoms without cognitive or motor disturbance do not warrant a diag- nosis of HAND. Non-lateralizing and mostly subtle signs of pyramidal, extrapyramidal, oculomotor and autonomous dysfunction may be present in advanced stages. The severity of HAND may be func- tionally categorized according to the Memorial Sloan Kettering scale (Table 4) (Price 1988). Table 2: Symptoms of HAND including history given by close relatives or companions Cognition Forgetfulness, difficulties concentrating, mental slowing (apprehension, processing) Emotional Loss of drive and initiative, withdrawal from social activities, failure to manage the financial and administrative aspects of one’s life. Depressive mood, emotional blunting Motor Slowing and impairment of fine movements (e. Finally mutism Neuro- Slowing of psychomotor speed (e. Occasionally accompanying polyneuropathy In the terminal stages: spastic tetraplegia and dual incontinence 630 Interdisciplinary Medicine Table 4: Severity of HAND (Memorial Sloan-Kettering (MSK) Scale) (Price 1988) Stage 0 (normal) normal mental and motor function Stage 0. Intellectual and social comprehension and output are at a rudimentary level; almost or completely mute; paraparetic or paraplegic with urinary and fecal incontinence Diagnostic workup Making the diagnosis of HAND requires a synopsis of clinical information and laboratory tests. No laboratory test result on its own can warrant a diagnosis of HAND. Rather, the diagnosis requires the exclusion of other conditions (Table 5). Psychological and behavioral as well as motor signs and symptoms may be subtle in the early stages. Motor signs are often encoun- tered in the later stages (Tables 2 and 3). Formal neuropsychological cognitive testing, the gold standard, should be done. This should encompass the domains verbal/ language, attention/working memory, abstraction/executive function, learning/ recall, speed of information processing, and motor skills (Mind Exchange Group 2013). Where a trained neuropsychologist is not available, the HIV dementia scale as an easy-to-use bedside instrument may be used, but its sensitivity and specificity are limited (Morgan 2008). Laboratory tests are mainly employed to exclude differential diagnoses. The MRI may show patchy, diffuse, and relatively symmetrical hyper- intense lesions in the white matter. In addition, atrophy with enlargement of the ventricles and the extraventricular CSF spaces may be seen. However, none of these findings are specific for HAND, and the disease may evolve with a normal MRI. Unlike in PML, the white matter lesions do not affect the cortical U-fibers, i. Edema and space occupying lesions are not compatible with HAND and should raise suspicion of other conditions. CSF analysis mostly shows a normal white cell count, and with severe immunosup- pression this may even be decreased. In patients with an at least partially effective ART, CSF pleocytosis may be seen, suggesting an immunological response to HIV in the context of immune reconstitution. Total protein and albumin concentrations may be slightly elevated (blood-brain barrier disruption). Oligoclonal bands and increased IgG index indicate autochthonous immunoglobulin production within the CNS. However, these findings are non-specific, and they are frequently present even in the asymptomatic stages of HIV infection. HIV-1-associated Neurocognitive Disorder (HAND) and Myelopathy 631 In untreated patients there is a weak but statistically significant correlation of (higher) CSF viral load with HAND. However, this association is no longer true for individu- als on ART (Mc Arthur 2004, Heaton 2011). The electroencephalogram (EEG) shows no or only mild signs of generalized slowing.

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With the screening test order erectafil 20mg, sensitivity has the highest priority (this way generic 20 mg erectafil visa, no infection should be missed) cheap erectafil online amex, while a high specificity is preferred for the confirmatory test buy erectafil line. Screening tests approved in Germany require a specificity of 99. That means that 16 The Basics one in 200 HIV-negative samples could have a false-reactive test result. False-reac- tive results are caused for example by stimulation of the immune system (e. To confirm a reactive screening test a Western Blot (immunoblot) analysis is typically carried out. Viral proteins (antigens) are separated by their molecular weight via electrophoresis and transferred to a membrane, which is then used as a test strip. An advance in terms of standardization is the so-called line blot produced by spraying recombinant HIV antigens directly onto a test membrane. The test strip is incubated with the serum or plasma. If HIV-specific antibodies are present, they bind to the antigen. Analogous to the ELISA the resulting antigen-antibody complex will become visible on the test strip using an enzyme-labeled second antibody and a correspon- ding substrate. According to the antibody specificities a corresponding band spectrum occurs on the test strip. Ideally, the laboratory will use a Western Blot, which also can detect and differenti- ate antibodies against HIV-2. In some assays, a synthetic peptide is used for HIV-2 screening. In case of a reactive HIV-2 band, this result must be confirmed by an HIV-2- specific Western Blot. Generally, Western Blot analysis leads to definite discrimina- tion between an HIV-1 or HIV-2 infection. However, due to the close relationship cross reactivity leading to antibody reactions against both virus types can occur. The final laboratory report should indicate if a patient is infected with HIV-1 or HIV-2 since the virus type has implications with regard to the antiretroviral treatment. The various HIV proteins are assigned to three functional groups (“p” – protein, “gp” – glycoprotein. The numbers refer to the molecular weight): Table 1: HIV antigens and functions Antigens Function HIV-1 HIV-2 Envelope proteins (env) gp160 gp140 Precursor of envelope proteins gp120 gp125 Outer envelope protein gp41 gp36 Transmembrane protein Polymerase proteins (pol) p66 p68 Reverse Transcriptase, RNaseH p51 p53 Reverse Transcriptase p32 p34 Endonuclease, integrase Core proteins (gag) p55 p56 Precursor of core proteins p24 p26 Inner core protein p17 p16 Outer core protein The formation of antibodies after infection follows a specific kinetic: while p24 and gp120 antibodies are detectable early, the p31 band usually occurs later in the course of infection (Fiebig 2003). With regard to the antibody specifics, the criteria for a positive result are not uniformly defined. In general, a Western Blot is considered positive when at least two or three bands are visible. For interpretation of a Western Blot the criteria specified by the manufacturer in the context of CE-marking are crucial. According to the German guidelines, based on the DIN 58969 Part 41 (“serodiagnosis of infectious diseases – immunoblot”), a test result is considered positive when antibodies to an env protein and also to a gag protein and/or a pol protein are detected. According to WHO criteria a Western Blot is positive when antibodies against at least 2 env proteins are HIV Testing 17 detectable. For example, a Western Blot with a gp120 and p24 band would be inter- preted borderline according to the WHO and positive according to the German criteria. However, a weak band spectrum, especially if “early” antibodies were detected, may indicate an early phase of an HIV infection and further tests such as PCR should be carried out (see below). Compared to a 4th generation screening test the p24 antigen is not included in the confirmatory test. In the case of “reactive screening test – negative confirmatory test”, acute HIV infection cannot be excluded when HIV-specific antibodies are not yet formed although the p24 antigen is present. If a patient is concerned regarding an acute infection (acute retro- viral syndrome, recent exchange of bodily fluids with an HIV+ person) the imple- mentation of an HIV PCR is useful. The PCR is also recommended in case of a highly positive screening and negative confirmatory test result. It is recommended to consult the laboratory to discuss the adequate procedure. To exclude sample confusion each first positive test result should be confirmed by examination of a second sample. If a patient is suspected to have an HIV infection, the result of viral load measurement can be used for confirmation (see chapter 6. In this case, a second serological test is not necessary. HIV PCR In addition to the serological test systems, molecular methods for detection of HIV RNA (nucleic acid amplifications tests, NAT) are available. PCR is the NAT most frequently used for HIV RNA detection. The quantitative detection of HIV RNA (a viral load determination) is one of the essential components of the monitoring of HIV infection (Wittek 2007, Thompson 2010). To increase the safety of blood products the HIV PCR is obliga- tory in the context of blood donation. Other indications for the use of the PCR are the exclusion of an HIV infection of newborns of HIV+ mothers (see below), the clarification of equivocal serological constellations or a suspected acute infection. According to new recommendations, PCR analysis may be used for confirmation of a reactive screening test result instead of a Western Blot. For this purpose, a PCR test is considered positive in case of a viral load above 1000 copies/ml. If the viral load amounts to less than 1000 copies/ml or the PCR is negative subsequent Western Blot analysis is obligatory (DVV/GfV 2015). However, the HIV PCR is not recommended as a screening test. Since false negative results are possible it cannot replace the serological screening test. Possible reasons for false negative results are as follows: 1. Commercially available HIV PCR tests usually do not cover HIV-2 (rare in Europe). HIV is characterized by a high degree of genetic diversity. In case of infection with a new or previously unknown variant sensitivity of the PCR may decrease due to mutations affecting the primer or probe binding sites. Through a so-called “dual target” PCR the risk of false negative test results due to sequence variability may be reduced (Chudy 2012; see also chapter 6. The “dual target” PCR is obligatory for screening blood donations. A small number of HIV+ patients can suppress viral replication in the absence of ART (“elite controllers”, prevalence less than 1%). Thus, despite serologically proven HIV infection a PCR test may be negative in those patients. The aim of the antiretroviral treatment is the reduction of the viral load below the detection limit. As a consequence, the use of a PCR as a HIV screening test in a successfully treated patient would lead to a false-negative testing result. Rapid tests Rapid HIV tests functionally correspond to a screening test, i. Rapid tests can be carried out quickly, easily and without any equipment expense and can therefore be used as so-called “point of care” tests. In addition to plasma and serum, full or capillary blood (from the fin- gertip or the ear lobe) is suitable as test material, so that no centrifuge is required. In some test systems urine or oral transudate (not saliva) may be used.

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