Tropical Parasitic Infections in Individuals Infected with HIV

Abstract

Purpose of Review:

Neglected tropical diseases share both geographic and socio-behavioral epidemiological risk factors with HIV infection. In this literature review, we describe interactions between parasitic diseases and HIV infection, with a focus on the impact of parasitic infections on HIV infection risk and disease progression, and the impact of HIV infection on clinical characteristics of tropical parasitic infections. We limit our review to tropical parasitic infections of the greatest public health burden, and exclude discussion of classic HIV-associated opportunistic infections that have been well reviewed elsewhere.

Recent Findings:

Tropical parasitic infections, HIV-infection, and treatment with antiretroviral therapy alter host immunity, which can impact susceptibility, transmissibility, diagnosis, and severity of both HIV and parasitic infections. These relationships have a broad range of consequences, from putatively increasing susceptibility to HIV acquisition, as in the case of schistosomiasis, to decreasing risk of protozoal infections through pharmacokinetic interactions between antiretroviral therapy and antiparasitic agents, as in the case of malaria. However, despite this intimate interplay in pathophysiology and a broad overlap in epidemiology, there is a general paucity of data on the interactions between HIV and tropical parasitic infections, particularly in the era of widespread antiretroviral therapy availability.

Summary:

Additional data are needed to motivate clinical recommendations for detection and management of parasitic infections in HIV-infected individuals, and to consider the implications of and potential opportunity granted by HIV treatment programs on parasitic disease control.

INTRODUCTION

Endemic HIV infection and neglected tropical diseases share a broad geographical distribution: over 25 million people in sub-Saharan Africa are living with HIV, and over 500 million people in the same region are believed to be infected with neglected parasitic diseases, including hookworm, schistosomiasis, ascariasis, and trichuriasis [1]. The interplay between tropical parasitic disease, HIV, their treatments, and the human host have important implications for host immunity, inflammatory responses, disease acquisition risk and disease severity [2–4]. As the epidemiology of HIV has shifted from a routinely fatal disease to a chronic, manageable condition for those with access to antiretroviral therapy (ART), there is an important need to describe relevant interactions between HIV infection, ART, and co-endemic parasites.

In this review, we intend to summarize published literature on interactions between tropical parasitic infections and HIV, with attention to impacts of parasitic infections on HIV disease progression and to the associations between HIV infection and parasitic disease acquisition, severity, and management (Table 1). We exclude discussion of known opportunistic infections commonly studied in the developed world, such as toxoplasmosis, pneumocystis, and gastrointestinal protozoa.

Table 1:

Associations between parasitic infections and HIV susceptibility and disease progression, helminth infection severity and relevant drug-drug interactions

Parasite	Helminth infection effect on HIV disease	HIV infection effect on helminth disease	Drug Interactions [186, 187]	References
Hookworm	↑ susceptibility (weak evidence)	↓ severity	Increased albendazole concentrations with PIs, decreased concentrations with EFV/NVP	[11, 16, 18, 21, 30, 31, 34–37, 39, 40, 44, 45]
Trichuris trichiura	↑ susceptibility (weak evidence)	-	Increased albendazole concentrations with PIs, decreased concentrations with EFV/NVP	[21, 44, 45]
Strongyloides stercoralis	-	↑ susceptibility (weak evidence)	Increased ivermectin concentrations with PIs, decreased concentrations with EFV/NVP; increased potential for CNS toxicity or Mazzotti-like reaction	[61, 62, 64]
Ascaris lumbricoides	↑ progression (weak evidence)	-	Increased albendazole concentrations with PIs, decreased concentrations with EFV/NVP	[12, 35, 44, 45, 49, 69, 70, 72, 74]
Wuchereria bancrofti	↑ susceptibility (weak evidence)	-	Limited data on DEC metabolism	[79–83, 86, 87]
Onchocerca volvulus	↑ progression (weak evidence)	↑ severity	Limited data on DEC metabolism	[93–97]
Loa loa	-	-	Increased albendazole concentrations with PIs, decreased concentrations with EFV/NVP	[44, 45]
Taenia solium	-	-	Increased albendazole/praziquantel concentrations with PIs, decreased concentrations with EFV/NVP	[44, 45, 103–105]
Echinococcus granulosis	-	↑ severity	Increased albendazole/mebendazole concentrations with PIs, decreased concentrations with EFV/NVP	[44, 45, 109, 110, 112–115]
Schistosomiasis	↑ susceptibility ↑ progression	-	Increased praziquantel concentrations with PIs, decreased concentrations with EFV/NVP	[118–121, 126–129]
Malaria	↑ susceptibility ↑ progression	↑ severity	Quinine, chloroquine, mefloquine, pyrimethamine-sulfadoxine, atovaquone-proguanil, doxycycline interactions with NVP, EFB, LPV/r, NFV, SQV/r; artemether-lumefantrine contraindicated with PIs	[4, 133–136]
Leishmania spp.	-	↑ susceptibility	Paromycin and miltefosine may increase GI side effects with co-administration of RTV containing PIs; Sodium stibogluconate may exacerbate pancreatitis with DDL; potential additive bone marrow toxicity with AZT, may stimulate HIV-1 replication	[150–154, 156, 158]
Chagas disease	-	↑ severity	Benznidazole/suramin/nifurtimox may increase peripheral neuropathy risk with DDL/D4T	[171, 172]
Sleeping sickness	↑ (HIV-2 only, weak evidence)	↑ severity	Pentamidine may increase pancreatitis with DDL; suramin may have additional nephrotoxicity with TDF; malarsoprol may increase CNS toxicity with EFV, nifurtimox may increase GI side effects with RTV containing PIs	[179–182]

SQV/r = saquinavir/ritonavir, NFV = nelfinavir, LPV/r = lopinavir/ritonavir, D4T = stavudine, DDL = didanosine, TDF = tenofovir disoproxil fumarate, AZT = zidovudine, EFV = efavirenz, NVP = nevirapine, PI = protease inhibitor

NEMATODE INFECTIONS

Hookworm

Human hookworm infection is caused by Ancylostoma duodenale in Northern Africa and India, and by Necator americanus in most of the rest of the tropics including sub-Saharan Africa and Southeast Asia. It is a clinically significant infection in the tropics, where it may cause iron-deficiency anemia, and, in cases with high worm burdens, has been associated with malnutrition and cognitive deficits among children[5]. In pregnant women living with HIV, hookworm infection has also been demonstrated to worsen anemia and increase the risk of maternal mortality[6–9]. There are 730 million people in the world living with hookworm infection, 130 million of whom are in sub-Saharan Africa [10, 11]. Estimates of HIV and hookworm co-infection vary by region, but in east Africa, have ranged from 2% −15% among people living with HIV (PLWH) [12–15]

Although incompletely described, the interactions between HIV and hookworm infections demonstrate the complex host-pathogen interplay at work in co-infections. For example, some have hypothesized that the HIV-induced T-helper (Th)-1 cell response might be protective against hookworm infection [16]. Depletion of T-cells in advanced HIV may also contribute through down regulation of IL-10 and TGF-β, which are known to play a beneficial role in hookworm infection [17]. Although supportive clinical data are sparse, a study of treatment-naive PLWH co-infected with tuberculosis (TB) found a lower prevalence of hookworm (12 vs 25%) and disease burden (49 vs 123 eggs/g of stool) in HIV-infected versus HIV-uninfected individuals, respectively [18]. Conversely, some evidence links hookworm infection to accelerated HIV disease progression through a favored Th2 immune response, consequent production of IL-10 and TGF-β, and expansion of T-cell HIV virion targets [19, 20]. This relationship has been postulated to induce an increased HIV-1 RNA viral load in hookworm co-infected individuals [21].

This shift from a Th1 to a Th2-favored immune response [17, 22] may also increase susceptibility to other intracellular infections, such as tuberculosis and cryptococcosis. For example, HIV-uninfected children in Tanzania with hookworm infection were more likely to be co-infected with latent TB than those without hookworm [23]. This relationship was seen despite the known decreased sensitivity of interferon-γ based latent tuberculosis tests seen in patients with helminthic infection[24]. Other studies have also demonstrated independent associations between helminth infection and tuberculosis risk [25–27].

Finally, interactions between hookworm infection and HIV-infection also appear to play out at the gut epithelial-lumen interface. Both hookworm and HIV infection have been demonstrated to induce microbial translocation, and resulting immune activation [28]. Although elevated, the Th2-mediated increases in IL-10 seen in hookworm infection may partially mitigate HIV-associated inflammation in those with co-infection [28, 29].

Given the complex interplay between HIV infection and hookworm infection, the impact of empiric helminth treatment on HIV disease progression has been an important and controversial area of study. While it has been suggested that there are beneficial effects of anthelmintic therapy on viral load and CD4+ T-cell concentration trajectories in ART-naïve STH co-infected individuals [30] others have found no such impact [31, 32]. Morawski et al. found that PLWH receiving ART were less likely to have hookworm co-infection. Additionally, those co-infected with hookworm had lower CD4+ T-cell counts, an this effect was sustained up to two years after ART initiation [33]. A case control study and two randomized controlled trials among ART ineligible PLWH demonstrated no benefit of either empiric or targeted treatment with albendazole on CD4+ T-cell count trajectories [34–36]. Lankowski et al. studied CD4+ T-cell recovery following anthelmintic treatment in PLWH initiating ART and found no immunologic benefit, although a sub-analysis restricted to women suggested a benefit of deworming [37]. Similarly, a randomized controlled trial of HIV infected pregnant women on ART in Rwanda found significant benefit in CD4+ T-cell count change and HIV RNA viral load reduction 48 weeks after treatment, regardless of confirmed helminth co-infection [38]. However, in a double-blind, randomized, placebo-controlled trial of ART naïve pregnant women in Uganda, there was no difference in HIV viral load after anthelmintic treatment [21]. In a meta-analysis of six studies on the subject, Sangare et al. did not demonstrate a significant benefit of deworming on markers of HIV-1 disease progression [39]. Another meta-analysis of eight observational and interventional trials analyzing effect of helminthic treatment on HIV viral load and CD4+ T-cell concentration found minimal impact of anti-helmintic therapy on either CD4+ T-cell concentration or viral load, whether treatment was empiric or for confirmed parasite infection [40]. Of the eight studies included in this meta-analysis, two included PLWH who had initiated ART, and only one demonstrated a positive effect of anthelmintic chemotherapy on CD4+ T-cell reconstitution [41]. Given the rapid expansion in ART availability in sub-Saharan Africa, further data that will further elucidate these clinical questions in the current era of ART are required.

World Health Organization (WHO) treatment recommendations for hookworm currently include presumptive treatment with 400 mg albendazole at a prevalence-dependent frequency for all at-risk persons (children, women of childbearing age and adults with additional occupational exposures) [42]. There are no specific guidelines for treating hookworm in the setting of HIV infection, and thus similar recommendations are presumed to apply for PLWH. However, there are important drug-drug interactions between HIV antiretroviral therapies and selected anthelminthic therapy, e.g. ritonavir-boosted protease inhibitors, which may decrease concentrations of albendazole [43] through induction of the CYP3A4 metabolic pathway (Table 1) [44, 45].

Trichuriasis

Trichuris trichiura, or whipworm, is commonly asymptomatic, but, in cases with a heavy worm burden, can cause of dysentery, anemia, and be associated with stunted growth[46, 47]. There are few data on interactions between whipworm and HIV infection, although in some regions prevalence of trichuriasis in PLWH have been reported to be up to 20% [48–50]. Trichuris infection has been associated with increased T-cell activation (HLA DR+ CD38+) and CD4+ CCR5 co-receptor expression, which may increase HIV susceptibility by increasing target effector cells [51]. Like hookworm infection, Trichuris infection has also been associated with higher viral load in pregnant women living with HIV [21], likely due to T-cell expansion promoting viral replication. Treatment for trichuriasis is either 400mg albendazole for three days, 100 mg mebendazole twice a day for three days, 200 mcg/kg/day for three days, and no alternate considerations have been made among PLWH.

Strongyloidiasis

In healthy individuals, Strongyloides stercoralis infection is often characterized as a benign chronic infection. However, various forms of immunosuppression increase risk of a severe and potentially fatal disseminated disease [52–54], where the organism is present in organs outside the skin, GI tract, or lungs. Higher rates of strongyloidiasis have been reported in PLWH versus uninfected individuals in Ethiopia, Brazil, Thailand, and South India [55–58], although more broad co-infection prevalence rates are not available in sub-Saharan Africa. Interestingly, disseminated disease, appears to be exceptionally rare in HIV infection, including in advanced disease [53]. Persistent anti-Strongyloides IgG in PLWH appears to maintain protection from disseminated strongyloidiasis, even at low CD4+ T-cell concentrations [53]. Nonetheless, because of the overlapping geographic risk, and the indication for corticosteroids with multiple HIV-related syndromes (e.g. tuberculous meningitis, Pneumocystis jiroveci pneumonia, immune reconstitution inflammatory syndromes) empiric therapy for strongyloidiasis infection may be indicated for this patient population to prevent morbidity from disseminated infection.

Although disseminated infection is uncommon in HIV, ART initiation in strongyloidiasis co-infection has been associated with an immune-reconstitution type syndrome [59–62], and HIV infection has been rarely associated with other complications of strongyloidiasis infection [51, 54, 59, 63] including invasion of the CNS [60]. Moreover, while data are relatively sparse, HIV infection has been described as an independent risk factor for strongyloidiasis. Small studies in Ethiopia, Thailand and India have all found estimated increased odds or prevalence of S. stercoralis infection among PLWH receiving ART [61, 62, 64]. Furthermore, one cross-sectional study in India exhibited a “dose-response” relationship between increasing infection rates and decreasing CD4+ T-cell concentrations [62]. However, ART use does not appear to significantly affect prevalence of S. stercoralis in PLWH [65]. Whether this is a true independent effect of HIV infection, or another confounding risk factor (e.g. socioeconomic status or health system strengthening) remains unknown.

Strongyloidiasis does not appear to affect the progression of HIV disease, and comparable baseline HIV disease markers CD4+ T-cell concentration and viral loads were observed in Strongyloides-infected versus uninfected individuals in PLWH [55, 58]. There are no specific recommendations on the timing of ART and or anthelmintic dosing of Strongyloides for PLWH. Empiric treatment should be strongly considered in patients from endemic regions who have an indication for corticosteroid use and/or other immunosuppressive therapies. Most recommendation a dose of ivermectin 200ug/kg daily for two days, or until stool exams are persistently negative in hyper-infection syndrome [66]. Caution is advised in regions with co-prevalent strongyloidiasis and loiasis, because treatment with ivermectin can cause a fatal encephalopathy in those with the latter [66].

Ascariasis

Ascaris lumbricoides is the most common soil transmitted helminth infection of humans globally [11, 67]. Ascaris infection is often asymptomatic, but can be complicated by intestinal and biliary obstruction due to worm migration, especially in children [68].

HIV disease stage does not appear to predispose individuals to ascariasis [12] and a similar prevalence of Ascaris has been shown in PLWH compared to HIV-uninfected individuals [49, 69]. Although a decreased prevalence of all STH, including Ascaris, was reported in Brazil in an era of ART expansion compared to the pre-ART era[70], these findings have not been validated in other settings, and concomitant advances in hygiene and sanitation could be responsible.

Ascaris infections are characterized by a dominant Th2 response [71], which, as described previously has been postulated to increase HIV susceptibility [51], although this has not been demonstrated by epidemiologic studies. There is evidence that untreated Ascaris infection can adversely affect HIV disease progression [72] through reduced production of Th1 cytokines [72, 73]. ART-naïve PLWH in southern Ethiopia treated for confirmed Ascaris infection had increases in CD4+ T-cell concentrations at 15 weeks and at 6-months [74]. Similarly, a randomized trial found a significant improvement in CD4+ T-cell concentrations among a sub-group of Ascaris and PLWH co-infection following treatment with albendazole compared to placebo [35]. The Center for Disease Control (CDC) recommends treating Ascariasis with a single dose of 400 mg albendazole, with no treatment specific guidelines for HIV-infected individuals [75].

Filarial Diseases

Lymphatic filariasis

Lymphatic filariasis is caused most commonly by the filarial nematode Wuchereria bancrofti. It has been decreasing in prevalence worldwide, largely due to elimination programs, but remains a significant public health problem in tropical regions [76]. In sub-Saharan Africa, an estimated 50 million people are infected with lymphatic filariasis [1, 77]. Prevalence of co-infection with HIV has been difficult to estimate, particularly in Asia and East Africa, where the disease burden is greatest [78]. Estimates from a study in Tanzania prior to mass treatment found an overall lymphatic filariasis prevalence of 25%, an HIV prevalence of 9%, and a co-infection prevalence of 42% in adults older than 18 years of age [79].

No association between lymphatic filariasis and HIV infection risk has been found in three studies in sub-Saharan Africa [79–81]. A single cross-sectional study demonstrated that lymphatic filariasis was correlated with HIV infection prevalence, but the results may have been influenced by confounding by age and gender [82]. The most compelling data come from a cohort study in southwestern Tanzania, which demonstrated increased risk of HIV acquisition over up to four years of observation [83]. The authors hypothesized that increased production of IL-4 and activated macrophages were responsible, however, more research into these relationships is needed[84, 85].

There is a mixed body of literature on the relationship between lymphatic filariasis infection, HIV disease stage, and response to anti-filiarial treatment. In a prospective case-control study of individuals with HIV and lymphatic filariasis co-infection, treatment with diethylcarbazine (DEC) and albendazole did not appear to affect HIV disease indices 1-year after treatment, such as HIV-1 viral load and CD4+ T-cell concentrations. Results were similar in a sub-analysis of ART naïve individuals[81]. A cross-sectional study comparing cytokine profiles in PLWH and HIV-uninfected individuals with and without lymphatic filariasis observed no difference treatment HIV viral load or CD4+ T-cell percentage prior to treatment with DEC [86]. However, a double blind, randomized controlled trial demonstrated that treatment of lymphatic filariasis with DEC in PLWH significantly reduces viral load [86]. A separate cross-sectional study of PLWH co-infected with lymphatic filariasis demonstrated that ART-treated individuals had a lower filarial load compared to ART naïve individuals and the burden of filarial antigenemia also decreased with increasing duration of ART [80].

Interestingly, therapy against lymphatic filariasis may be more efficacious in PLWH. One study demonstrated significantly increased filarial specific IgG3 in PLWH and significantly lower concentrations of IgG4, a biomarker of filarial infection, 12 weeks after lymphatic filariasis treatment compared to HIV-uninfected individuals [87]. The authors hypothesize that the increased levels of IgG3 was due to an HIV-induced Th1 response, while the reduction in IgG4 corresponded with circulating filarial antigen before and after treatment. Further research is required to determine if these results can offer insights into improving lymphatic filariasis therapy. Combination treatment with albendazole and ivermectin, an alternative regimen recommended by the WHO in select populations, appears to be as efficacious in reducing filarial burden in PLWH as it is in people without HIV infection [83, 88]. One case of death due to “severe HIV infection” was reported in a randomized clinical trial demonstrating efficacy of doxycycline over placebo through targeting of the Wolbachia endosymbiont, a finding which may require further investigation [89].

Onchocerciasis

River blindness, caused by the filarial worm Onchocerca volvulus, is the second leading cause of infectious blindness world-wide [90]. Since neglected tropical diseases were included in the Millennium Development Goals in 2000, onchocerciasis eradication efforts have been successful in Colombia (2013), Ecuador (2014), Mexico (2015)[91], and Guatemala (2016) [92]. Onchocerciasis remains an endemic in Uganda, Brazil, Ethiopia, Nigeria, Sudan, and Venezuela, where over 6.7 million PLWH reside [77]. HIV infection has been postulated to alter the presentation of Onchocerca infections, with worse dermatologic involvement among infected individuals [93]. Additionally, HIV infection has been shown to reduce antibody responses to onchocerciasis [94] potentially leading to slower clearance of filarial infection.

Onchocerciasis may alter immune responses to HIV infection. This was demonstrated in one in-vitro study, where HIV viral replication increased after stimulation of PBMCs isolated from individuals with filarial infections, compared to parasite-free individuals [84]. However, in that same study, there was no difference in expression of proteins known to facilitate HIV infection such as CCR5 or CXCR4 co-receptors in those with and without prior filarial infection. Conversely, PBMCs from PLWH versus HIV-uninfected controls, had an impaired specific response to onchocerciasis, and were less efficient in producing interleukin IL-4 and IL-5, which are involved in the immune control of onchocerciasis [95]. These findings are consistent with the fact that a vigorous Th2 response is responsible for parasite death and may hasten resultant blindness [96, 97].

Loiasis

Loa loa, the filarial eye worm, remains endemic in many West African countries. There are few studies of interactions between HIV and Loa loa. One study in Gabon demonstrated that PLWH taking trimethoprim-sulfamethoxazole prophylaxis were less likely to have L. loa co-infection [42]. Trimethoprim, which inhibits dihydrofolate reductase, an enzyme encoded in the L. loa genome, has been suggested as a potential target for drug therapy in various parasitic infections [98–100]. Future work is be needed to assess if folate-inhibiting agents might protect against L. loa, and the mechanisms by which these agents may work.

CESETODES

Taeniasis

Neurocysticercosis is believed to be responsible for approximately 30% of epilepsy cases in sub-Saharan Africa, affecting between 760,000 to 2,460,000 people in the region [101]. HIV infection can complicate diagnosis of neurocysticercosis, because the differential diagnosis of intracerebral lesions is broad in PLWH and serologic assays are less sensitive in cerebrospinal fluid [102]. While a handful of published cases describe ART-related IRIS exacerbating neurocysticercosis infections, there is insufficient evidence to support this as a common phenomenon [103]. However, there are suggestions that HIV-related immune dysregulation influences clinical manifestations of neurocysticercosis. Cerebral inflammation in response to cystic rupture is partially dependent on Th1-mediated immune responses, which require active CD4+ T-cell populations [103, 104]. Similarly, Th1-mediated immune activity prevents multi-cyst infection. Th2 responses, which are more vigorous as CD4+ T-cells are depleted, have been associated with subclinical multi-cyst neurocysticercosis [105].

A combination of albendazole, praziquantel, and corticosteroids, which is informed by clinical severity, cyst viability, cyst location, and cyst number, is the standard of care for treatment of neurocysticercosis [106, 107]. Some have suggested that treatment thresholds for neurocysticercosis should be lowered among PLWH[107, 108]. As in all conditions requiring prolonged steroid use, careful attention to risk for Pneumocystis jiroveci pneumonia, disseminated Strongyloides, active tuberculosis, hepatitis B virus reactivation, and other diseases with reactivation potential should be considered along with the initiation of corticosteroid therapy.

Echinococcosis

Few cases of echinococcosis and HIV co-infection have been reported. A single case series of four patients suggested that advanced HIV disease might increase the risk of more rapid cyst development and growth [109]. As previously discussed, HIV infection is believed to result in a Th2-dominant immune response. This Th2 milieu is hypothesized to create a more suitable host environment for echinococcus growth [110]. For example, individuals infected with inactive cysts have been shown to have an exclusively Th1 immune response, whereas patients with active cystic disease showed a mixed Th1/Th2 response [111] These data suggest that the HIV-induced Th2 imbalance may promote active cystic growth of the echinococcus helminth. Other reports of Echinococcus granulosus infection in PLWH indicate that extra-hepatic disease might be more common in this population [112–115]. However, a review article in South Africa did not show a statistically significant difference in the prevalence of disseminated cystic echinococcosis in HIV infected verses uninfected adults [116].

TREMATODES

Schistosomiasis

Human schistosomiasis is caused by the trematodes Schistosoma haematobium, Schistosoma mansoni, Schistosoma japonicum, and Schistosoma mekongi, and affects 240 million people worldwide mostly in tropical and subtropical regions[117]. Schistosomiasis can remain asymptomatic for decades, but can progress to a chronic sclerosing condition with hepatic or genitourinary involvement if untreated. Urogenital schistosomiasis, caused by S. haematobium, manifests as hematuria, fibrosis of the bladder and ureters, and eventually, bladder cancer. Women with urogenital schistosomiasis may have genital lesions, vaginal bleeding and dyspareunia. Some studies have suggested that urogenital schistosomiasis is a risk factor for HIV infection, and that the treatment and/or prevention of Schistosoma infections can potential aid in HIV disease control[118]. Evidence supporting this theory includes findings of increased concentrations of HIV target cells surrounding S. mansoni parasites in vaginal tissue[119], and a resulting increased vascularization of the vagina and cervix in female urogenital schistosomiasis [120]. Females with urogenital schistosomiasis have also been hypothesized to have higher HIV transmission rates due to compromised vaginal epithelial tissue and increased HIV target cells [121]. A recent (completed but unpublished) clinical trial in Uganda seeks to test the impact that Schistosoma infection and treatment may have on HIV susceptibility (ClinicalTrials.gov: NCT02878564).

Some studies have found reduced worm burdens in those with co-infection compared to those without HIV infection [122]. Other studies have hypothesized that the life cycle of the worm is dependent on a T-cell response which is diminished during HIV infection. However, egg expulsion also appears to be dependent on T-cell mediated pathways, and could explain the decreased egg expulsion in PLWH. Egg retention does not appear to alter disease severity [123]. However, ecologic studies have suggested that regions with high prevalence of both HIV and schistosomiasis also have a high prevalence of renal dysfunction [2, 3]. A case-control study of children living with HIV and their uninfected siblings demonstrated schistosomiasis as an independent correlate of renal dysfunction [124].

Finally, there is evidence that schistosomiasis infection can accelerate HIV disease progression and hamper HIV treatment responses [125], as demonstrated by longer time to viral load suppression and reduced CD4+ T-cell expansion following ART initiation [126, 127]. Although immediate treatment of schistosomiasis did not improve viral suppression in a randomized controlled trial comparing early versus delayed praziquantel therapy among PLWH receiving ART, those randomized to delayed praziquantel had higher viral loads and lower CD4+ T-cell concentrations after three months of observation [128]. This effect has been attributed to increasing Th2 activity in response to treatment with praziquantel and worm killing [127–129]. There are no HIV-specific related treatment recommendations for schistosomiasis, and 40–60 mg/kg of praziquantel, depending on the species, is typically recommended [130].

PROTOZOA

Malaria

Globally, malaria prevalence and fatalities have decreased by 18% and 37% respectively, since 2000 [131]. However, malaria remains an important public health issue due to its high associated mortality among children, and the recurrence of drug resistance to newer artemisinin-based therapies [132]. PLWH have a higher burden of malaria, and, when infected, could have more severe anemia [4] and worse outcomes [133, 134]. Malaria infection also appears to increase HIV target cell expansion, and consequentially increases HIV viral replication in ART-naïve PCP-prophylaxis-naïve individuals [135, 136].

A randomized controlled trial of cotrimoxazole prophylaxis in children infected with HIV demonstrated a protective affect against malaria, compared to HIV-uninfected children not on prophylaxis [137]. Similar studies confirmed a protective effect of cotrimoxazole prophylaxis, and that the effect was no longer present after discontinuation [138, 139]. There is also mounting interest in the use of boosted protease inhibitors in the prevention of malaria in endemic areas, through improved pharmacokinetics of antimalarial drugs [140–145]. A randomized controlled trial in Uganda confirmed that protease inhibitor-based ART, compared to non-nucleoside based regimens, was associated with a decreased incidence of malaria, and that this benefit was related to prolonged duration of therapeutic lumefantrine drug levels [146]. Partially based on these findings, WHO HIV guidelines recommend cotrimoxazole prophylaxis in all PLWH in malaria-endemic areas, and boosted protease inhibitors as first line antiretroviral therapy in infants and children with HIV[147].

Leishmaniasis

The three principal clinical manifestations of leishmaniasis include cutaneous, mucocutaneous, and visceral syndromes, which are caused by over 20 different Leishmania spp. In east Africa, 40% of patients with visceral leishmaniasis are co-infected with HIV [148]. Although leishmaniasis is typically transmitted by the sand-fly vector, Leishmania transmission has been observed through needle sharing in PLWH [149]. There are many HIV-specific clinical features of Leishmania infection, and the visceral manifestation is considered an opportunistic infection [150, 151]. PLWH appear to be at risk for diffuse cutaneous leishmaniasis, treatment resistant disease, and recurrent infections [152, 153], but also appear to more commonly have asymptomatic disease [154]. Atypical manifestations seen in PLWH, especially those with advanced immunosuppression, include absence of the classic triad of fever, hepatomegaly, and splenomegaly, and the presence ofamastigotes in atypical tissues including gastrointestinal tract, skin, tonsils and lung [155]. Although HIV infection has been shown to significantly increase risk for death from visceral leishmaniasis [156, 157], ART appears to be protective against leishmaniasis among PLWH [154] and likely reduces rates of relapse [158]. Specifically, protease inhibitors might have direct activity against the parasite, although more research is needed [148, 159]. Alternatively, prophylaxis for visceral leishmaniasis relapse in PLWH with monthly infusions of pentamidine has demonstrated preliminary success by reducing relapse free survival from 50–100% in historical controls to 29% [160].

Although the cutaneous and mucocutaneous forms are diagnosed with biopsy and pathology, visceral forms can be challenging to diagnose, and serologic tests may have a lower sensitivity in PLWH due to a lack of a humoral immune response [150, 161]. Treatment for visceral and severe cutaneous forms of leishmaniasis involves liposomal or standard amphotericin B. However, in many areas where amphotericin B is not available, pentavalent antimony is still recommended. Although resistance to liposomal amphotericin B has been reported in HIV infection [162], there is insufficient evidence to warrant alternate recommendations for PLWH. Many recommendations include secondary prophylaxis until immune reconstitution, as defined by a CD4+ T-cell concentration >250 cells/mcL [163–165]. The FDA recently approved miltefosine for all types of leishmaniasis, which was well tolerated in a small (n=5) study among PLWH[166].

Trypanosomiasis

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is an infection characterized by acute and chronic phases, ultimately leading to cardiomyopathy and, less commonly, esophageal dilatation in 10–30% of untreated patients [167, 168]. Reactivated Chagas disease is considered an AIDS defining illness in Brazil [169, 170]. PLWH are more likely to have detectable parasitemia on peripheral blood smears in chronic Chagas infection than HIV-uninfected individuals[171], and there are reports of higher mortality due to chronic Chagas disease with cardiac involvement in PLWH [172]. To our knowledge, there are no reports of Chagas and HIV-related IRIS upon ART initiation. As in leishmaniasis, there is some evidence that protease inhibitors may have direct activity against trypanosomes. Nelfinavir and lopinavir target aspartic peptidases and proteasomes of T. cruzi [140, 173]. Treatment for Chagas disease is typically recommended for younger patients, those with acute infection and those without significant cardiomyopathy, with benznidazole and nifurtimox as preferred agents [174, 175]. In contrast, treatment of chronic disease in those with advanced cardiomyopathy remains controversial [176]. No HIV-specific treatment recommendations are currently available.

Sleeping sickness is caused by the Trypanosoma brucei rhodesiense (East African Sleeping Sickness) protozoa in southern and eastern Africa and Trypanosoma brucei gambiense (West African Sleeping Sickness) in western and central Africa. The majority of cases are due to T. brucei gambiense and reported in the Democratic Republic of the Congo (DRC). Infection is characterized in two stages: the first stage involves the blood and lymph nodes, and the central nervous system is invaded by the second stage [177]. Data describing associations between African Sleeping Sickness and HIV infection are sparse. Some research has recommended that serology-based HIV testing should be avoided until after treatment of trypanosomiasis because false positive HIV tests are reportedly more common during active infection [178]. HIV infection did not impact outcomes in individuals with second stage sleeping sickness in Tanzania[179]. Early clinical studies in Zaire (presently DRC) prior to ART availability suggested that although HIV did not increase the risk factor of sleeping sickness acquisition, it was associated with trypanosomiasis treatment failure [180, 181]. Some evidence has also suggested that African sleeping sickness may predispose individuals to HIV-2 infection, and additionally lower CD4+ T-cell concentrations[182]. Treatment for East African Sleeping Sickness involves suramin for early stage disease and melarsoprol (preferably co-administered with corticosteroids) for those with central nervous system involvement. In regions where onchocerciasis is endemic, additional caution should be used before administration of suramin. For West African Sleeping Sickness, treatment includes either monotherapy with pentamidine for 7–10 days for first stage disease or intravenous eflornithine for two weeks with or without nifurtimox for infections with CNS involvement [183]. Neither disease has HIV-specific guidelines for treatment.

CONCLUSION

Both HIV infection and tropical parasitic infections are common in sub-Saharan Africa, and cause significant morbidity and mortality. Despite this, associations between HIV and most neglected tropical infections remain understudied, and poorly understood, and opportunities for integrated care are potentially overlooked [184]. As HIV increasingly becomes a prevalent, chronic condition in much of the region, additional attention to the interplay between the two is warranted, particularly regarding preventing transmission of HIV infection, ensuring optimal long-term health of PLWH, and strengthening efforts to eradicate and control neglected infections[185].